Journal articles on the topic 'HIV vaccine; adjuvants'
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1
Berendam, Stella J., Papa K. Morgan-Asiedu, Riley J. Mangan, Shuk Hang Li, Holly Heimsath, Kan Luo, Alan D. Curtis, et al. "Different adjuvanted pediatric HIV envelope vaccines induced distinct plasma antibody responses despite similar B cell receptor repertoires in infant rhesus macaques." PLOS ONE 16, no. 12 (December 31, 2021): e0256885. http://dx.doi.org/10.1371/journal.pone.0256885.
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Different HIV vaccine regimens elicit distinct plasma antibody responses in both human and nonhuman primate models. Previous studies in human and non-human primate infants showed that adjuvants influenced the quality of plasma antibody responses induced by pediatric HIV envelope vaccine regimens. We recently reported that use of the 3M052-SE adjuvant and longer intervals between vaccinations are associated with higher magnitude of antibody responses in infant rhesus macaques. However, the impact of different adjuvants in HIV vaccine regimens on the developing infant B cell receptor (BCR) repertoire has not been studied. This study evaluated whether pediatric HIV envelope vaccine regimens with different adjuvants induced distinct antigen-specific memory B cell repertoires and whether specific immunoglobulin (Ig) immunogenetic characteristics are associated with higher magnitude of plasma antibody responses in vaccinated infant rhesus macaques. We utilized archived preclinical pediatric HIV vaccine studies PBMCs and tissue samples from 19 infant rhesus macaques immunized either with (i) HIV Env protein with a squalene adjuvant, (ii) MVA-HIV and Env protein co-administered using a 3-week interval, (iii) MVA-HIV prime/ protein boost with an extended 6-week interval between immunizations, or (iv) with HIV Env administered with 3M-052-SE adjuvant. Frequencies of vaccine-elicited HIV Env-specific memory B cells from PBMCs and tissues were similar across vaccination groups (frequency range of 0.06–1.72%). There was no association between vaccine-elicited antigen-specific memory B cell frequencies and plasma antibody titer or avidity. Moreover, the epitope specificity and Ig immunogenetic features of vaccine-elicited monoclonal antibodies did not differ between the different vaccine regimens. These data suggest that pediatric HIV envelope vaccine candidates with different adjuvants that previously induced higher magnitude and quality of plasma antibody responses in infant rhesus macaques were not driven by distinct antigen-specific memory BCR repertoires.
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Moser, B. A., R. C. Steinhardt, Y. Escalante-Buendia, D. A. Boltz, K. M. Barker, B. J. Cassaidy, M. G. Rosenberger, S. Yoo, B. G. McGonnigal, and A. P. Esser-Kahn. "Increased vaccine tolerability and protection via NF-κB modulation." Science Advances 6, no. 37 (September 2020): eaaz8700. http://dx.doi.org/10.1126/sciadv.aaz8700.
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Improving adjuvant responses is a promising pathway to develop vaccines against some pathogens (e.g., HIV or dengue). One challenge in adjuvant development is modulating the inflammatory response, which can cause excess side effects, while maintaining immune activation and protection. No approved adjuvants yet have the capability to independently modulate inflammation and protection. Here, we demonstrate a method to limit inflammation while retaining and often increasing the protective responses. To accomplish this goal, we combined a partial selective nuclear factor kappa B (NF-kB) inhibitor with several current adjuvants. The resulting vaccines reduce systemic inflammation and boost protective responses. In an influenza challenge model, we demonstrate that this approach enhances protection. This method was tested across a broad range of adjuvants and antigens. We anticipate these studies will lead to an alternative approach to vaccine formulation design that may prove broadly applicable to a wide range of adjuvants and vaccines.
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Kozlowski, Pamela A., and Anna Aldovini. "Mucosal Vaccine Approaches for Prevention of HIV and SIV Transmission." Current Immunology Reviews 15, no. 1 (April 12, 2019): 102–22. http://dx.doi.org/10.2174/1573395514666180605092054.
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Optimal protective immunity to HIV will likely require that plasma cells, memory B cells and memory T cells be stationed in mucosal tissues at portals of viral entry. Mucosal vaccine administration is more effective than parenteral vaccine delivery for this purpose. The challenge has been to achieve efficient vaccine uptake at mucosal surfaces, and to identify safe and effective adjuvants, especially for mucosally administered HIV envelope protein immunogens. Here, we discuss strategies used to deliver potential HIV vaccine candidates in the intestine, respiratory tract, and male and female genital tract of humans and nonhuman primates. We also review mucosal adjuvants, including Toll-like receptor agonists, which may adjuvant both mucosal humoral and cellular immune responses to HIV protein immunogens.
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Louis, Lumena, Megan C. Wise, Hyeree Choi, Daniel O. Villarreal, Kar Muthumani, and David B. Weiner. "Designed DNA-Encoded IL-36 Gamma Acts as a Potent Molecular Adjuvant Enhancing Zika Synthetic DNA Vaccine-Induced Immunity and Protection in a Lethal Challenge Model." Vaccines 7, no. 2 (May 22, 2019): 42. http://dx.doi.org/10.3390/vaccines7020042.
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Identification of novel molecular adjuvants which can boost and enhance vaccine-mediated immunity and provide dose-sparing potential against complex infectious diseases and for immunotherapy in cancer is likely to play a critical role in the next generation of vaccines. Given the number of challenging targets for which no or only partial vaccine options exist, adjuvants that can address some of these concerns are in high demand. Here, we report that a designed truncated Interleukin-36 gamma (IL-36 gamma) encoded plasmid can act as a potent adjuvant for several DNA-encoded vaccine targets including human immunodeficiency virus (HIV), influenza, and Zika in immunization models. We further show that the truncated IL-36 gamma (opt-36γt) plasmid provides improved dose sparing as it boosts immunity to a suboptimal dose of a Zika DNA vaccine, resulting in potent protection against a lethal Zika challenge.
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Ozorowski, Gabriel, Albert Cupo, Michael Golabek, Michelle LoPiccolo, Thomas A. Ketas, Matt Cavallary, Christopher A. Cottrell, P. J. Klasse, Andrew B. Ward, and John P. Moore. "Effects of Adjuvants on HIV-1 Envelope Glycoprotein SOSIP TrimersIn Vitro." Journal of Virology 92, no. 13 (April 18, 2018): e00381-18. http://dx.doi.org/10.1128/jvi.00381-18.
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ABSTRACTNative-like, soluble, recombinant SOSIP trimers of various designs and based on severalenvgenes of human immunodeficiency virus type 1 (HIV-1) are being tested as immunogens in different animal models. These experiments almost always involve coformulating the trimers with an adjuvant to boost the magnitude of the immune responses. One factor relevant to the choice of an adjuvant is that it should not physically damage the immunogen or impede its ability to present relevant epitopes. As examples, an adjuvant formulation that includes harsh detergents could disrupt the structural integrity of a trimer, and any charged compounds in the formulation could bind to countercharged regions of the trimer and physically occlude nearby epitopes. While a few adjuvants have been tested for their potential effects on SOSIP trimersin vitro, there has been no systematic study. Here, we have assessed how nine different adjuvants of various compositions affect SOSIP trimers of the BG505 and B41 genotypes. We used negative-stain electron microscopy, thermal denaturation, and gel electrophoresis to evaluate effects on trimer integrity and immunoassays to measure effects on the presentation of various epitopes. We conclude that most of the tested adjuvants are benign from these perspectives, but some raise grounds for concern. An acidified alum formulation is highly disruptive to trimer integrity, and a DNA-based polyanionic CpG oligodeoxynucleotide adjuvant binds to trimers and occludes the trimer apex epitope for the PGT145 neutralizing antibody. The methods described here should be generalizable to protein subunit vaccines targeting various pathogens.IMPORTANCEAdjuvant formulations increase the magnitude of immune responses to vaccine antigens. They are critically important for formulation of HIV-1 envelope glycoprotein (Env) vaccines intended to induce antibody production, as Env proteins are otherwise only very weakly immunogenic. The HIV-1 vaccine field now uses the well-defined structures of trimeric Env glycoproteins, like SOSIPs, to present multiple known epitopes for broad and potent neutralizing human antibodies in a native-like conformation. Successful adjuvant formulations must not disrupt how the trimers are folded, as that could adversely affect their performance as immunogens. We studied whether the various adjuvants most commonly used in animal experiments affect the integrity of two different SOSIP trimersin vitro. Most adjuvant classes are not problematic, but an aluminum sulfate formulation is highly damaging, as it exposes trimers to acidic pH and a nucleic acid-based adjuvant can bind to the trimer and block access to a key neutralizing epitope.
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Gupta, Sachin, Emily S. Clark, James M. Termini, Justin Boucher, Saravana Kanagavelu, Celia C. LeBranche, Sakhi Abraham, David C. Montefiori, Wasif N. Khan, and Geoffrey W. Stone. "DNA Vaccine Molecular Adjuvants SP-D-BAFF and SP-D-APRIL Enhance Anti-gp120 Immune Response and Increase HIV-1 Neutralizing Antibody Titers." Journal of Virology 89, no. 8 (January 28, 2015): 4158–69. http://dx.doi.org/10.1128/jvi.02904-14.
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ABSTRACTBroadly neutralizing antibodies (bNAbs) specific for conserved epitopes on the HIV-1 envelope (Env) are believed to be essential for protection against multiple HIV-1 clades. However, vaccines capable of stimulating the production of bNAbs remain a major challenge. Given that polyreactivity and autoreactivity are considered important characteristics of anti-HIV bNAbs, we designed an HIV vaccine incorporating the molecular adjuvants BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) with the potential to facilitate the maturation of polyreactive and autoreactive B cells as well as to enhance the affinity and/or avidity of Env-specific antibodies. We designed recombinant DNA plasmids encoding soluble multitrimers of BAFF and APRIL using surfactant protein D as a scaffold, and we vaccinated mice with these molecular adjuvants using DNA and DNA-protein vaccination strategies. We found that immunization of mice with a DNA vaccine encoding BAFF or APRIL multitrimers, together with interleukin 12 (IL-12) and membrane-bound HIV-1 Env gp140, induced neutralizing antibodies against tier 1 and tier 2 (vaccine strain) viruses. The APRIL-containing vaccine was particularly effective at generating tier 2 neutralizing antibodies following a protein boost. These BAFF and APRIL effects coincided with an enhanced germinal center (GC) reaction, increased anti-gp120 antibody-secreting cells, and increased anti-gp120 functional avidity. Notably, BAFF and APRIL did not cause indiscriminate B cell expansion or an increase in total IgG. We propose that BAFF and APRIL multitrimers are promising molecular adjuvants for vaccines designed to induce bNAbs against HIV-1.IMPORTANCERecent identification of antibodies that neutralize most HIV-1 strains has revived hopes and efforts to create novel vaccines that can effectively stimulate HIV-1 neutralizing antibodies. However, the multiple immune evasion properties of HIV have hampered these efforts. These include the instability of the gp120 trimer, the inaccessibility of the conserved sequences, highly variable protein sequences, and the loss of HIV-1-specific antibody-producing cells during development. We have shown previously that tumor necrosis factor (TNF) superfamily ligands, including BAFF and APRIL, can be multitrimerized using the lung protein SP-D (surfactant protein D), enhancing immune responses. Here we show that DNA or DNA-protein vaccines encoding BAFF or APRIL multitrimers, IL-12p70, and membrane-bound HIV-1 Env gp140 induced tier 1 and tier 2 neutralizing antibodies in a mouse model. BAFF and APRIL enhanced the immune reaction, improved antibody binding, and increased the numbers of anti-HIV-1 antibody-secreting cells. Adaptation of this vaccine design may prove useful in designing preventive HIV-1 vaccines for humans.
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Ceglia, Valentina, Sandy Zurawski, Monica Montes, Aurelie Bouteau, Zhiqing Wang, Jerome Ellis, Mitchell Kroll, Botond Z. Igyarto, Yves Levy, and Gerard Zurawski. "Dendritic cell targeting anti-CD40 antibody-CD40L-HIV-1 vaccines are adjuvant intrinsic." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 167.2. http://dx.doi.org/10.4049/jimmunol.204.supp.167.2.
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Abstract Soluble CD40L and agonistic anti-CD40 monoclonal antibody are adjuvants used in vaccination settings. Vaccines based on anti-CD40 antibodies fused to HIV-1 antigens are in clinical development. Studies with current anti-CD40-based dendritic cell (DC) targeting vaccines show that co-administration of an adjuvant is needed for maximal immune responses. We show that by fusing CD40L to CD40-targeting antibodies, activation of DCs concomitant with antigen uptake and processing is maximized, and this provides a context CD40-targeting vaccines with intrinsic adjuvant activity. Direct fusion of CD40L to L or H chain C-termini results in CD40 agonists with ‘superagonist’ properties. Especially on DCs, both potency and efficacy for induction of cytokine secretion and activation markers is greatly enhanced compared to known strong agonists like Pfizer’s anti-CD40 CP-870-89 antibody. This potency was maintained by anti-CD40-CD40L constructs fused to HIV-1 antigens from Gag, Nef, and Pol regions (HIV5pep). Anti-CD40-CD40L-HIV5pep preferentially expanded CD8+ T cells from HIV-1+ donor PBMCs compared to the same antibody-antigen fusions without attached CD40L. Anti-CD40-CD40L-TEα and anti-CD40-TEα both evoked robust proliferation of TEα-specific CD4+ T cells in human CD40 transgenic mice, but only anti-CD40-CD40L-TEα vaccine elicited TEα-specific CD4+ T cells producing IFNγ. Also, anti-CD40-CD40L-Env gp140 vaccine without adjuvant in human CD40 transgenic mice elicited stronger anti-Env gp140 antibody responses than anti-CD40-Env gp140 vaccine. Thus superagonist anti-CD40 antibodies directly fused to the natural ligand show great advantage in inducing immune responses without the use of an extrinsic adjuvant.
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Bui, Cac T., Lisa M. Shollenberger, Yvonne Paterson, and Donald A. Harn. "Schistosoma mansoni Soluble Egg Antigens Enhance Listeria monocytogenes Vector HIV-1 Vaccine Induction of Cytotoxic T Cells." Clinical and Vaccine Immunology 21, no. 9 (July 2, 2014): 1232–39. http://dx.doi.org/10.1128/cvi.00138-14.
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ABSTRACTVaccines are an important public health measure for prevention and treatment of diseases. In addition to the vaccine immunogen, many vaccines incorporate adjuvants to stimulate the recipient's immune system and enhance vaccine-specific responses. While vaccine development has advanced from attenuated organism to recombinant protein or use of plasmid DNA, the development of new adjuvants that safely increase immune responses has not kept pace. Previous studies have shown that the complex mixture of molecules that comprise saline soluble egg antigens (SEA) fromSchistosoma mansonieggs functions to promote CD4+T helper 2 (Th2) responses. Therefore, we hypothesized that coadministration of SEA with aListeriavector HIV-1 Gag (Lm-Gag) vaccine would suppress host cytotoxic T lymphocyte (CTL) and T helper 1 (Th1) responses to HIV-1 Gag epitopes. Surprisingly, instead of driving HIV-1 Gag-specific responses toward Th2 type, we found that coadministration of SEA with Lm-Gag vaccine significantly increased the frequency of gamma interferon (IFN-γ)-producing Gag-specific Th1 and CTL responses over that seen in mice administered Lm-Gag only. Analysis of the functionality and durability of vaccine responses suggested that SEA not only enlarged different memory T cell compartments but induced functional and long-lasting vaccine-specific responses as well. These results suggest there are components in SEA that can synergize with potent inducers of strong and durable Th1-type responses such as those toListeria. We hypothesize that SEA contains moieties that, if defined, can be used to expand type 1 proinflammatory responses for use in vaccines.
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Shollenberger, Lisa M., Stephanie K. Norwood, and Zachary J. Bement. "Development of alternative vaccination strategies to overcome Tc1 vaccine failure caused by chronic schistosomiasis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 167.13. http://dx.doi.org/10.4049/jimmunol.204.supp.167.13.
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Abstract It is a global public health imperative to develop vaccine strategies that produce effective cell-mediated immunity in schistosome-endemic areas, such as sub-Saharan Africa, where HIV infection is common. Vaccine delivery techniques effective in immune-suppressed populations are critical to combating infectious diseases in these already compromised groups. It is well-known that immune suppression, such as by chronic schistosome infection, can cause Tc1/Th1 type vaccines to fail. Listeria, a strong inducer of cell-mediated immunity, can overcome the Th2 biasing and immune suppression caused by schistosome infection. However, safety concerns cause reluctance among the vaccine community and the public to incorporate this vector into immunization programs. Since neither DNA nor the Listeria vaccine vector are ideal for clinical translation, and Gag is likely not the ideal HIV vaccine antigen, we are using this system as a model for enumeration of Tc1 responses (IFNγ+ CD8+ cytotoxic T lymphocytes, CTL); CTLs are likely necessary components of functional responses for next-generation vaccines targeting diseases that currently lack effective vaccines (HIV, TB, malaria). Here, we investigate why DNA vaccine vectors fail during chronic schistosomiasis when Listeria vaccine vectors can generate robust CTL responses to HIV Gag. Specifically, we are examining live bacteria as adjuvants for an episomally expressed or concurrently administered DNA vaccine for HIV Gag. This project is one step toward our overall goal, which is to generate cell-mediated vaccine immunity in schistosome-infected, immune-suppressed patients.
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Vijayan, Mohapatra, Uthaman, and Park. "Recent Advances in Nanovaccines Using Biomimetic Immunomodulatory Materials." Pharmaceutics 11, no. 10 (October 14, 2019): 534. http://dx.doi.org/10.3390/pharmaceutics11100534.
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The development of vaccines plays a vital role in the effective control of several fatal diseases. However, effective prophylactic and therapeutic vaccines have yet to be developed for completely curing deadly diseases, such as cancer, malaria, HIV, and serious microbial infections. Thus, suitable vaccine candidates need to be designed to elicit appropriate immune responses. Nanotechnology has been found to play a unique role in the design of vaccines, providing them with enhanced specificity and potency. Nano-scaled materials, such as virus-like particles, liposomes, polymeric nanoparticles (NPs), and protein NPs, have received considerable attention over the past decade as potential carriers for the delivery of vaccine antigens and adjuvants, due to their beneficial advantages, like improved antigen stability, targeted delivery, and long-time release, for which antigens/adjuvants are either encapsulated within, or decorated on, the NP surface. Flexibility in the design of nanomedicine allows for the programming of immune responses, thereby addressing the many challenges encountered in vaccine development. Biomimetic NPs have emerged as innovative natural mimicking biosystems that can be used for a wide range of biomedical applications. In this review, we discuss the recent advances in biomimetic nanovaccines, and their use in anti-bacterial therapy, anti-HIV therapy, anti-malarial therapy, anti-melittin therapy, and anti-tumor immunity.
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Gómez, Carmen Elena, Beatriz Perdiguero, Michela Falqui, María Q. Marín, Martina Bécares, Carlos Óscar S. Sorzano, Juan García-Arriaza, Mariano Esteban, and Susana Guerra. "Enhancement of HIV-1 Env-Specific CD8 T Cell Responses Using Interferon-Stimulated Gene 15 as an Immune Adjuvant." Journal of Virology 95, no. 2 (October 28, 2020): e01155-20. http://dx.doi.org/10.1128/jvi.01155-20.
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ABSTRACTInduction of the endogenous innate immune system by interferon (IFN) triggers the expression of many proteins that serve like alarm bells in the body, activating an immune response. After a viral infection, one of the genes activated by IFN induction is the IFN-stimulated gene 15 (ISG15), which encodes a ubiquitin-like protein that undergoes a reversible posttranslational modification (ISGylation). ISG15 protein can also act unconjugated, intracellularly and secreted, acting as a cytokine. Although ISG15 has an essential role in host defense responses to microbial infection, its role as an immunomodulator in the vaccine field remains to be defined. In this investigation, we showed that ISG15 exerts an immunomodulatory role in human immunodeficiency virus (HIV) vaccines. In mice, after priming with a DNA-ISG15 vector mixed with a DNA expressing HIV-1 gp120 (DNA-gp120), followed by a booster with a modified vaccinia virus Ankara (MVA) vector expressing HIV-1 antigens, both wild-type ISG15-conjugated (ISG15-wt) and mutant unconjugated (ISG15-mut) proteins act as immune adjuvants by increasing the magnitude and quality of HIV-1-specific CD8 T cells, with ISG15-wt providing better immunostimulatory activity than ISG15-mut. The HIV-1 Env-specific CD8 T cell responses showed a predominant T effector memory (TEM) phenotype in all groups. Moreover, the amount of DNA-gp120 used to immunize mice could be reduced 5-fold after mixing with DNA-ISG15 without affecting the potency and the quality of the HIV-1 Env-specific immune responses. Our study clearly highlights the potential use of the IFN-induced ISG15 protein as immune adjuvant to enhance immune responses to HIV antigens, suggesting that this molecule might be exploitable for prophylactic and therapeutic vaccine approaches against pathogens.IMPORTANCE Our study described the potential role of ISG15 as an immunomodulatory molecule in the optimization of HIV/AIDS vaccine candidates. Using a DNA prime–MVA boost immunization protocol, our results indicated an increase in the potency and the quality of the HIV-1 Env-specific CD8 T cell response. These results highlight the adjuvant potency of ISG15 to elicit improved viral antigen presentation to the immune system, resulting in an enhanced HIV-1 vaccine immune response. The DNA-ISG15 vector could find applicability in the vaccine field in combination with other nucleic acid-based vector vaccines.
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Buglione-Corbett, Rachel, Kim Pouliot, Robyn Marty-Roix, Kim West, Shixia Wang, Egil Lien, and Shan Lu. "Adjuvant-dependent cytokine profiles in the context of a DNA prime-protein boost HIV vaccine (113.23)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 113.23. http://dx.doi.org/10.4049/jimmunol.188.supp.113.23.
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Abstract Heterologous prime-boost vaccination approaches have emerged as a promising strategy to generate protective immunity against a variety of pathogens in animal and human studies. Our previous studies demonstrated that HIV-1 gp120 DNA vaccine prime-protein boost elicits improved neutralizing antibody responses. To understand the mechanisms that regulate the immune responses in prime-boost vaccination strategy, current studies were designed to define the cytokine profiles associated with different adjuvants used in such regimens. A polyvalent vaccine DP6-001, including gp120 antigens from 5 different primary viral isolates, was used as the model vaccine. Any influence of endotoxin associated with DNA plasmid preparation was first excluded, as regular DNA preparations did not elicit different immune response when tested in vivo against endotoxin-free DNA preparations. Next we studied the effects of several adjuvants, QS-21, alum, and MPL, on the immunogenicity of DP6-001 in a mouse model. gp120-specific antibody and T cell responses, and innate cytokine production, were monitored at time points after immunizations and at termination. Our results indicate that different adjuvants may generate unique cytokine profiles and improve the immunogenicity of DP6-001. This study may provide valuable information in selection of an adjuvant for inclusion in future prime-boost vaccination strategies, with the goal of enhancing immunogenicity while minimizing reactogenicity.
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Cheng, Liang, Guangming Li, Dan Li, Zheng Zhang, Feng Li, Sandra Zurawski, Gerard Zurawski, Yves Levy, and Lishan Su. "A novel therapeutic vaccination delays cART-resistant HIV-1 reservoir rebound in HIV-1 infected humanized mice." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 76.7. http://dx.doi.org/10.4049/jimmunol.196.supp.76.7.
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Abstract Highly active anti-retroviral therapy (HAART) prevents disease progression but does not eradiate HIV, and this therapy often does not fully restore HIV patients’ immune status. Thus, there remains an unmet need to develop new stratagies to “cure” (eradication or control of HIV-1 with no ART) individuals of HIV infection. Modulating host’s cellular immune response is a promising way to cure HIV infection. We have developed a prototype vaccine with a string of 5 highly conserved T cell epitope rich regions of HIV-1 Gag, Nef and Pol fused to a monoclonal antibody that bind the antigen presenting cell activating receptor CD40(aCD40.HIV5pep). Here we use the humanized mouse model to evaluate the therapeutic effect of the aCD40.HIV5pep vaccine to chronic HIV infection. We first screened a batch of novel TLR adjuvants which have the potential to enhance the immunogenicity of aCD40.HIV5pep in vivo and showed that when vaccinated with Poly I:C as adjuvants, aCD40.HIV5pep can induce human CD8+ CTL response in humanized mice. Interestingly, we found that Poly I:C treatment can activate cART-resistant HIV-1 reservoir in in the presence of cART in chronically infected humanized mice. Finally, we showed that Poly I:C plus aCD40.HIV5pep therapeutic vaccination significantly delayed HIV virus rebound in HIV-1 infected humanized mice after withdraw of cART treatment. Our proof-of-concept study in humanized mice has significant implication for the development of therapeutic vaccine to cue HIV infection.
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Laher, Fatima, Linda-Gail Bekker, Nigel Garrett, Erica M. Lazarus, and Glenda E. Gray. "Review of preventative HIV vaccine clinical trials in South Africa." Archives of Virology 165, no. 11 (August 14, 2020): 2439–52. http://dx.doi.org/10.1007/s00705-020-04777-2.
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AbstractNew HIV infections continue relentlessly in southern Africa, demonstrating the need for a vaccine to prevent HIV subtype C. In South Africa, the country with the highest number of new infections annually, HIV vaccine research has been ongoing since 2003 with collaborative public-private-philanthropic partnerships. So far, 21 clinical trials have been conducted in South Africa, investigating seven viral vectors, three DNA plasmids, four envelope proteins, five adjuvants and three monoclonal antibodies. Active vaccine candidates have spanned subtypes A, B, C, E and multi-subtype mosaic sequences. All were well tolerated. Four concepts were investigated for efficacy: rAd5-gag/pol/nef showed increased HIV acquisition in males, subtype C ALVAC/gp120/MF59 showed no preventative efficacy, and the trials for the VRC01 monoclonal antibody and Ad26.Mos4.HIV/subtype C gp140/ aluminum phosphate are ongoing. Future trials are planned with DNA/viral vector plus protein combinations in concert with pre-exposure prophylaxis, and sequential immunization studies with transmitted/founder HIV envelope to induce broadly neutralizing antibodies. Finally, passive immunization trials are underway to build on the experience with VRC01, including single and combination antibody trials with an antibody derived from a subtype-C-infected South African donor. Future consideration should be given to the evaluation of novel strategies, for example, inactivated-whole-virus vaccines.
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Kutzler, Michele, Noshin Kathuria, Ashley Curatola, Getrude Makurumidze, Devon Myles, Kar Muthumani, Albert Sylvester, et al. "CCR10 expression is required for immunogenicity of a HIV-1env DNA vaccine encoding CCL28 to enhance HIV-1env-specific IgG and IgA at relevant mucosal sites (VAC7P.986)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 141.31. http://dx.doi.org/10.4049/jimmunol.192.supp.141.31.
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Abstract Development of a vaccine that drives anti-viral mucosal B cell responses is critical for protection against HIV-1 infection. It is currently unknown whether triggering CCR10/CCL28 pathways in a DNA-based vaccine results in induction of HIV-1env specific B cell immunity at mucosal sites of infection. We hypothesized that co-immunization with HIV-1env/CCL28 molecular adjuvant would augment B cell responses at gastrointestinal and vaginal sites and require CCR10. CCL28 co-immunized WT mice displayed a significant enhancement of HIV-1env specific antibody titers in serum, feces and vaginal washes, and enhanced HIV-1 specific IgA responses were abrogated in CCR10KO mice. CCL28 co-immunization did not increase the breadth of linear B cell epitopes in WT mice, but augmented the dominant epitopes elicited by antigen immunization alone. The frequency of splenic and intestinal IgA+CD19+B220+CD138+CCR10+ plasmablasts was augmented in the CCL28 co-immunized WT mice over antigen-only immunized WT controls. The physiological relevance of these findings was confirmed in a NHP model of intravaginal SIVsmE660 challenge in which CCL28 co-immunization resulted in significant increases in serum/vaginal IgG/IgA, decrease in peak viral loads, significant suppression of viral titers over 120 days, and recovery of CD4 T cells. These data support a role for CCL28 in targeting protective anti-viral B cells to mucosal sites when delivered as molecular adjuvants for HIV-1env DNA-based vaccines.
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Bement, Zachary James, Stephanie K. Norwood, and Lisa M. Shollenberger. "Understanding the early steps of the adaptive immune response to differentially-effective vaccines during chronic schistosomiasis." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 167.14. http://dx.doi.org/10.4049/jimmunol.204.supp.167.14.
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Abstract Schistosomiasis is the second most burdensome parasitic disease in the world after malaria and is classified as a neglected tropical disease. Schistosomiasis is caused by an immunomodulatory helminth that can induce a Th2 biased response, which can cause Tc1 vaccine failure. Interestingly, the use of pathogenic Listeria monocytogenes vaccine vectors can overcome this failure through an unknown mechanism. Despite the promise of Listeria-vectored vaccines, there is reluctance among the vaccine community and the public to incorporate this vector into immunization programs, due to safety concerns. Here we ask what the question: Why do Listeria vaccines function when other methods, such as DNA vaccination, fail? To answer this question, we use bone-marrow derived dendritic cells (BMDCs) in vitro to model the development of vaccine immunity during the early steps of the adaptive immune response. To compare the immune environment in naïve and schistosome-infected vaccine recipients, we compare responses from both reactogenic DC1 and tolerogenic DC2 dendritic cells, respectively. The DC1 and DC2 subtypes are exposed to a DNA vaccine for HIV, a Listeria vaccine expressing the HIV-1 Gag protein, or left untouched. Through immunological and transcriptomic approaches, we examine these cells for their activation state and functionality; these results will help to elucidate the mechanism/s by which Listeria vectors can overcome schistosome-induced vaccine failure and identify unique molecular vaccine adjuvants functional in schistosome-endemic areas.
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Kilgore, Katie M., Megan K. Murphy, Samantha L. Burton, Katherine S. Wetzel, S. Abigail Smith, Peng Xiao, Sharmila Reddy, et al. "Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope." Journal of Virology 89, no. 16 (May 27, 2015): 8130–51. http://dx.doi.org/10.1128/jvi.01221-14.
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ABSTRACTAntibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector- and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen.IMPORTANCEMany in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodies with greater neutralization breadth.
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Casimiro, Danilo R., Ling Chen, Tong-Ming Fu, Robert K. Evans, Michael J. Caulfield, Mary-Ellen Davies, Aimin Tang, et al. "Comparative Immunogenicity in Rhesus Monkeys of DNA Plasmid, Recombinant Vaccinia Virus, and Replication-Defective Adenovirus Vectors Expressing a Human Immunodeficiency Virus Type 1 gag Gene." Journal of Virology 77, no. 11 (June 1, 2003): 6305–13. http://dx.doi.org/10.1128/jvi.77.11.6305-6313.2003.
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ABSTRACT Cellular immune responses, particularly those associated with CD3+ CD8+ cytotoxic T lymphocytes (CTL), play a primary role in controlling viral infection, including persistent infection with human immunodeficiency virus type 1 (HIV-1). Accordingly, recent HIV-1 vaccine research efforts have focused on establishing the optimal means of eliciting such antiviral CTL immune responses. We evaluated several DNA vaccine formulations, a modified vaccinia virus Ankara vector, and a replication-defective adenovirus serotype 5 (Ad5) vector, each expressing the same codon-optimized HIV-1 gag gene for immunogenicity in rhesus monkeys. The DNA vaccines were formulated with and without one of two chemical adjuvants (aluminum phosphate and CRL1005). The Ad5-gag vector was the most effective in eliciting anti-Gag CTL. The vaccine produced both CD4+ and CD8+ T-cell responses, with the latter consistently being the dominant component. To determine the effect of existing antiadenovirus immunity on Ad5-gag-induced immune responses, monkeys were exposed to adenovirus subtype 5 that did not encode antigen prior to immunization with Ad5-gag. The resulting anti-Gag T-cell responses were attenuated but not abolished. Regimens that involved priming with different DNA vaccine formulations followed by boosting with the adenovirus vector were also compared. Of the formulations tested, the DNA-CRL1005 vaccine primed T-cell responses most effectively and provided the best overall immune responses after boosting with Ad5-gag. These results are suggestive of an immunization strategy for humans that are centered on use of the adenovirus vector and in which existing adenovirus immunity may be overcome by combined immunization with adjuvanted DNA and adenovirus vector boosting.
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Díaz-Dinamarca, Diego A., Michelle L. Salazar, Byron N. Castillo, Augusto Manubens, Abel E. Vasquez, Fabián Salazar, and María Inés Becker. "Protein-Based Adjuvants for Vaccines as Immunomodulators of the Innate and Adaptive Immune Response: Current Knowledge, Challenges, and Future Opportunities." Pharmaceutics 14, no. 8 (August 11, 2022): 1671. http://dx.doi.org/10.3390/pharmaceutics14081671.
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New-generation vaccines, formulated with subunits or nucleic acids, are less immunogenic than classical vaccines formulated with live-attenuated or inactivated pathogens. This difference has led to an intensified search for additional potent vaccine adjuvants that meet safety and efficacy criteria and confer long-term protection. This review provides an overview of protein-based adjuvants (PBAs) obtained from different organisms, including bacteria, mollusks, plants, and humans. Notably, despite structural differences, all PBAs show significant immunostimulatory properties, eliciting B-cell- and T-cell-mediated immune responses to administered antigens, providing advantages over many currently adopted adjuvant approaches. Furthermore, PBAs are natural biocompatible and biodegradable substances that induce minimal reactogenicity and toxicity and interact with innate immune receptors, enhancing their endocytosis and modulating subsequent adaptive immune responses. We propose that PBAs can contribute to the development of vaccines against complex pathogens, including intracellular pathogens such as Mycobacterium tuberculosis, those with complex life cycles such as Plasmodium falciparum, those that induce host immune dysfunction such as HIV, those that target immunocompromised individuals such as fungi, those with a latent disease phase such as Herpes, those that are antigenically variable such as SARS-CoV-2 and those that undergo continuous evolution, to reduce the likelihood of outbreaks.
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Staats, Herman F., and Francis A. Ennis. "IL-1 Is an Effective Adjuvant for Mucosal and Systemic Immune Responses When Coadministered with Protein Immunogens." Journal of Immunology 162, no. 10 (May 15, 1999): 6141–47. http://dx.doi.org/10.4049/jimmunol.162.10.6141.
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Abstract Mucosal immunization with soluble protein Ag alone may induce Ag-specific tolerance, whereas mucosal immunization with Ag in the presence of a mucosal adjuvant may induce Ag-specific systemic and mucosal humoral and cell-mediated immune responses. The most widely used and studied mucosal adjuvant is cholera toxin (CT). Although the mechanism of adjuvanticity of CT is not completely understood, it is known that CT induces mucosal epithelial cells to produce the proinflammatory cytokines IL-1, IL-6, and IL-8 and up-regulates macrophage production of IL-1 and the costimulatory molecule B7.2. Because IL-1 may duplicate many of the activities of CT, we evaluated IL-1α and IL-1β for their ability to serve as mucosal adjuvants when intranasally administered with soluble protein Ags. IL-1α and IL-1β were as effective as CT for the induction of Ag-specific serum IgG, vaginal IgG and IgA, systemic delayed-type hypersensitivity, and lymphocyte proliferative responses when intranasally administered with soluble protein Ag. Our results indicate that IL-1α and IL-1β may be useful as mucosal vaccine adjuvants. Such an adjuvant may be useful, and possibly required, for vaccine-mediated protection against pathogens that infect via the mucosal surfaces of the host such as HIV.
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Wilson, Cara C., Walter C. Olson, Thomas Tuting, Charles R. Rinaldo, Michael T. Lotze, and Walter J. Storkus. "HIV-1-Specific CTL Responses Primed In Vitro by Blood-Derived Dendritic Cells and Th1-Biasing Cytokines." Journal of Immunology 162, no. 5 (March 1, 1999): 3070–78. http://dx.doi.org/10.4049/jimmunol.162.5.3070.
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Abstract Vaccine strategies designed to elicit strong cell-mediated immune responses to HIV Ags are likely to lead to protective immunity against HIV infection. Dendritic cells (DC) are the most potent APCs capable of priming both MHC class I- and II-restricted, Ag-specific T cell responses. Utilizing a system in which cultured DC from HIV-seronegative donors were used as APC to present HIV-1 Ags to autologous T cells in vitro, the strength and specificity of primary HIV-specific CTL responses generated to exogenous HIV-1 Nef protein as well as intracellularly expressed nef transgene product were investigated. DC expressing the nef gene were able to stimulate Nef-specific CTL, with T cells from several donors recognizing more than one epitope restricted by a single HLA molecule. Primary Nef-specific CTL responses were also generated in vitro using DC pulsed with Nef protein. T cells primed with Nef-expressing DC (via protein or transgene) were able to lyse MHC class I-matched target cells pulsed with defined Nef epitope peptides as well as newly identified peptide epitopes. The addition of Th1-biasing cytokines IL-12 or IFN-α, during priming with Nef-expressing DC, enhanced the Nef-specific CTL responses generated using either Ag-loading approach. These results suggest that this in vitro vaccine model may be useful in identifying immunogenic epitopes as vaccine targets and in evaluating the effects of cytokines and other adjuvants on Ag-specific T cell induction. Successful approaches may provide information important to the development of prophylactic HIV vaccines and are envisioned to be readily translated into clinical DC-based therapeutic vaccines for HIV-1.
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Wille-Reece, Ulrike, Barbara J. Flynn, Karin Loré, Richard A. Koup, Aaron P. Miles, Allan Saul, Ross M. Kedl, et al. "Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates." Journal of Experimental Medicine 203, no. 5 (April 24, 2006): 1249–58. http://dx.doi.org/10.1084/jem.20052433.
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There is a remarkable heterogeneity in the functional profile (quality) of T cell responses. Importantly, the magnitude and/or quality of a response required for protection may be different depending on the infection. Here, we assessed the capacity of different Toll like receptor (TLR)-binding compounds to influence T helper cell (Th)1 and CD8+ T cell responses when used as adjuvants in nonhuman primates (NHP) with HIV Gag as a model antigen. NHP were immunized with HIV Gag protein emulsified in Montanide ISA 51, an oil-based adjuvant, with or without a TLR7/8 agonist, a TLR8 agonist, or the TLR9 ligand cytosine phosphate guanosine oligodeoxynucleotides (CpG ODN), and boosted 12 wk later with a replication-defective adenovirus-expressing HIV-Gag (rAD-Gag). Animals vaccinated with HIV Gag protein/Montanide and CpG ODN or the TLR7/8 agonist had higher frequencies of Th1 responses after primary immunization compared to all other vaccine groups. Although the rAD-Gag boost did not elevate the frequency of Th1 memory cytokine responses, there was a striking increase in HIV Gag-specific CD8+ T cell responses after the boost in all animals that had received a primary immunization with any of the TLR adjuvants. Importantly, the presence and type of TLR adjuvant used during primary immunization conferred stability and dramatically influenced the magnitude and quality of the Th1 and CD8+ T cell responses after the rAD-Gag boost. These data provide insights for designing prime-boost immunization regimens to optimize Th1 and CD8+ T cell responses.
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Chamcha, Venkateswarlu, Pradeep B. J. Reddy, Sunil Kannanganat, Courtney Wilkins, Sailaja Gangadhara, Vijayakumar Velu, Richard Green, et al. "Strong TH1-biased CD4 T cell responses are associated with diminished SIV vaccine efficacy." Science Translational Medicine 11, no. 519 (November 20, 2019): eaav1800. http://dx.doi.org/10.1126/scitranslmed.aav1800.
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Activated CD4 T cells are a major target of HIV infection. Results from the STEP HIV vaccine trial highlighted a potential role for total activated CD4 T cells in promoting HIV acquisition. However, the influence of vaccine insert-specific CD4 T cell responses on HIV acquisition is not known. Here, using the data obtained from four macaque studies, we show that the DNA prime/modified vaccinia Ankara boost vaccine induced interferon γ (IFNγ+) CD4 T cells [T helper 1 (TH1) cells] rapidly migrate to multiple tissues including colon, cervix, and vaginal mucosa. These mucosal TH1 cells persisted at higher frequencies and expressed higher density of CCR5, a viral coreceptor, compared to cells in blood. After intravaginal or intrarectal simian immunodeficiency virus (SIV)/simian-human immunodeficiency virus (SHIV) challenges, strong vaccine protection was evident only in animals that had lower frequencies of vaccine-specific TH1 cells but not in animals that had higher frequencies of TH1 cells, despite comparable vaccine-induced humoral and CD8 T cell immunity in both groups. An RNA transcriptome signature in blood at 7 days after priming immunization from one study was associated with induction of fewer TH1-type CD4 cells and enhanced protection. These results demonstrate that high and persisting frequencies of HIV vaccine–induced TH1-biased CD4 T cells in the intestinal and genital mucosa can mitigate beneficial effects of protective antibodies and CD8 T cells, highlighting a critical role of priming immunization and vaccine adjuvants in modulating HIV vaccine efficacy.
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Tunggal, Hillary Claire, Paul Veness Munson, Megan Ashley O’Connor, Nika Hajari, Sandra Elizabeth Dross, Debra Bratt, James Thomas Fuller, Kenneth Bagley, and Deborah Heydenburg Fuller. "Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs." PLOS ONE 16, no. 6 (June 17, 2021): e0253265. http://dx.doi.org/10.1371/journal.pone.0253265.
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A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.
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Matchett, William E., Goda Baddage Rakitha Malewana, Haley Mudrick, Michael J. Medlyn, and Michael A. Barry. "Genetic Adjuvants in Replicating Single-Cycle Adenovirus Vectors Amplify Systemic and Mucosal Immune Responses against HIV-1 Envelope." Vaccines 8, no. 1 (February 2, 2020): 64. http://dx.doi.org/10.3390/vaccines8010064.
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Most infections occur at mucosal surfaces. Providing a barrier of protection at these surfaces may be a useful strategy to combat the earliest events in infection when there are relatively few pathogens to address. The majority of vaccines are delivered systemically by the intramuscular (IM) route. While IM vaccination can drive mucosal immune responses, mucosal immunization at intranasal (IN) or oral sites can lead to better immune responses at mucosal sites of viral entry. In macaques, IN immunization with replicating single-cycle adenovirus (SC-Ads) and protein boosts generated favorable mucosal immune responses. However, there was an apparent “distance effect” in generating mucosal immune responses. IN immunization generated antibodies against HIV envelope (env) nearby in the saliva, but weaker responses in samples collected from the distant vaginal samples. To improve on this, we tested here if SC-Ads expressing genetic adjuvants could be used to amplify antibody responses in distant vaginal samples when they are codelivered with SC-Ads expressing clade C HIV env immunogen. SC-Ads env 1157 was coadministered with SC-Ads expressing 4-1BBL, granulocyte macrophage colony-stimulating factor (GMCSF), IL-21, or Clostridoides difficile (C. diff.) toxin fragments by IN or IM routes. These data show that vaginal antibody responses were markedly amplified after a single immunization by the IN or IM routes, with SC-Ad expressing HIV env if this vaccine is complemented with SC-Ads expressing genetic adjuvants. Furthermore, the site and combination of adjuvants appear to “tune” these antibody responses towards an IgA or IgG isotype bias. Boosting these priming SC-Ad responses with another SC-Ad or with SOSIP native-like env proteins markedly amplifies env antibody levels in vaginal washes. Together, this data may be useful in informing the choice of route of delivery adenovirus and peptide vaccines against HIV-1.
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AKAGI, Takami, Masanori BABA, and Mitsuru AKASHI. "Development of Vaccine Adjuvants Using Polymeric Nanoparticles and Their Potential Applications for Anti-HIV Vaccine." YAKUGAKU ZASSHI 127, no. 2 (February 1, 2007): 307–17. http://dx.doi.org/10.1248/yakushi.127.307.
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Melo, Alanne Rayssa da Silva, Larissa Silva de Macêdo, Maria da Conceição Viana Invenção, Ingrid Andrêssa de Moura, Marco Antonio Turiah Machado da Gama, Cristiane Moutinho Lagos de Melo, Anna Jéssica Duarte Silva, Marcus Vinicius de Aragão Batista, and Antonio Carlos de Freitas. "Third-Generation Vaccines: Features of Nucleic Acid Vaccines and Strategies to Improve Their Efficiency." Genes 13, no. 12 (December 4, 2022): 2287. http://dx.doi.org/10.3390/genes13122287.
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Gene immunization comprises mRNA and DNA vaccines, which stand out due to their simple design, maintenance, and high efficacy. Several studies indicate promising results in preclinical and clinical trials regarding immunization against ebola, human immunodeficiency virus (HIV), influenza, and human papillomavirus (HPV). The efficiency of nucleic acid vaccines has been highlighted in the fight against COVID-19 with unprecedented approval of their use in humans. However, their low intrinsic immunogenicity points to the need to use strategies capable of overcoming this characteristic and increasing the efficiency of vaccine campaigns. These strategies include the improvement of the epitopes’ presentation to the system via MHC, the evaluation of immunodominant epitopes with high coverage against emerging viral subtypes, the use of adjuvants that enhance immunogenicity, and the increase in the efficiency of vaccine transfection. In this review, we provide updates regarding some characteristics, construction, and improvement of such vaccines, especially about the production of synthetic multi-epitope genes, widely employed in the current gene-based vaccines.
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Sundling, Christopher, Karin Schön, Andreas Mörner, Mattias N. E. Forsell, Richard T. Wyatt, Rigmor Thorstensson, Gunilla B. Karlsson Hedestam, and Nils Y. Lycke. "CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization." Journal of General Virology 89, no. 12 (December 1, 2008): 2954–64. http://dx.doi.org/10.1099/vir.0.2008/005470-0.
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Strategies to induce potent and broad antibody responses against the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Env) at both systemic and mucosal sites represent a central goal for HIV-1 vaccine development. Here, we show that the non-toxic CTA1-DD adjuvant promoted mucosal and systemic humoral and cell-mediated immune responses following intranasal (i.n.) immunizations with trimeric or monomeric forms of HIV-1 Env in mice and in non-human primates. Env-specific IgG subclasses in the serum of immunized mice reflected a balanced Th1/Th2 type of response. Strikingly, i.n. immunizations with Env and the CTA1-DD adjuvant induced substantial levels of mucosal anti-Env IgA in bronchial alveolar lavage and also detectable levels in vaginal secretions. By contrast, parenteral immunizations of Env formulated in Ribi did not stimulate mucosal IgA responses, while the two adjuvants induced a similar distribution of Env-specific IgG-subclasses in serum. A single parenteral boost with Env in Ribi adjuvant into mice previously primed i.n. with Env and CTA1-DD, augmented the serum anti-Env IgG levels to similar magnitudes as those observed after three intraperitoneal immunizations with Env in Ribi. The augmenting potency of CTA1-DD was similar to that of LTK63 or CpG oligodeoxynucleotides (ODN). However, in contrast to CpG ODN, the effect of CTA1-DD and LTK63 appeared to be independent of MyD88 and toll-like receptor signalling. This is the first demonstration that CTA1-DD augments specific immune responses also in non-human primates, suggesting that this adjuvant could be explored further as a clinically safe mucosal vaccine adjuvant for humoral and cell-mediated immunity against HIV-1 Env.
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Shollenberger, Lisa M., and Donald A. Harn. "Vaccine self-assembling immune matrix is a non-viral delivery platform that improves overall vaccine performance while maintaining safety and stability." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 147.2. http://dx.doi.org/10.4049/jimmunol.198.supp.147.2.
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Abstract Vaccination remains the most effective public health tool to prevent infectious disease. Many vaccines are marginally effective, and are less so when administered to immune-compromised populations. To enhance vaccine immunogenicity, we exploited the biphasic property of the (RADA)4 synthetic oligopeptide to create a new vaccine delivery method, VacSIM® (vaccine self-assembling immune matrix). Vaccine components are mixed with the VacSIM® solution for injection, after which the (RADA)4 peptides self-assemble into hydrated nanofiber gel-matrices, forming a vaccine depot with the vaccine antigens in the aqueous phase, allowing for slow-release of vaccine components over time. Thus, we have a non-viral, inert, biodegradable delivery system, not requiring formulation that can deliver various types of vaccines. We hypothesize that slow-release of vaccine components provides antigen persistence, driving enhanced vaccine-specific responses that are improved in both quantity and quality. We have tested VacSIM® with live bacterial vectors, inactivated virus and multiple recombinant protein vaccines. VacSIM® delivery of different protein immunogens, including Hepatitis B and HIV Envelope, is superior to delivery in licensed and unlicensed adjuvants and requires only a single injection. VacSIM® improves existing vaccines by reducing the number of injections needed, improving vaccine performance, especially in difficult-to-protect populations like the elderly and immune compromised, and reducing unwelcome side effects. VacSIM® can be stockpiled and stored without a cold chain, which is especially beneficial in resource-limited settings where vaccine access and compliance are issues.
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Gary, Ebony N., and Michele A. Kutzler. "Defensive Driving: Directing HIV-1 Vaccine-Induced Humoral Immunity to the Mucosa with Chemokine Adjuvants." Journal of Immunology Research 2018 (December 13, 2018): 1–14. http://dx.doi.org/10.1155/2018/3734207.
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A myriad of pathogens gain access to the host via the mucosal route; thus, vaccinations that protect against mucosal pathogens are critical. Pathogens such as HIV, HSV, and influenza enter the host at mucosal sites such as the intestinal, urogenital, and respiratory tracts. All currently licensed vaccines mediate protection by inducing the production of antibodies which can limit pathogen replication at the site of infection. Unfortunately, parenteral vaccination rarely induces the production of an antigen-specific antibody at mucosal surfaces and thus relies on transudation of systemically generated antibody to mucosal surfaces to mediate protection. Mucosa-associated lymphoid tissues (MALTs) consist of a complex network of immune organs and tissues that orchestrate the interaction between the host, commensal microbes, and pathogens at these surfaces. This complexity necessitates strict control of the entry and exit of lymphocytes in the MALT. This control is mediated by chemoattractant chemokines or cytokines which recruit immune cells expressing the cognate receptors and adhesion molecules. Exploiting mucosal chemokine trafficking pathways to mobilize specific subsets of lymphocytes to mucosal tissues in the context of vaccination has improved immunogenicity and efficacy in preclinical models. This review describes the novel use of MALT chemokines as vaccine adjuvants. Specific attention will be placed upon the use of such adjuvants to enhance HIV-specific mucosal humoral immunity in the context of prophylactic vaccination.
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Decroix, Nipa, Perayot Pamonsinlapatham, Cahn P. Quan, and Jean-Pierre Bouvet. "Impairment by Mucosal Adjuvants and Cross-Reactivity with Variant Peptides of the Mucosal Immunity Induced by Injection of the Fusion Peptide PADRE-ELDKWA." Clinical Diagnostic Laboratory Immunology 10, no. 6 (November 2003): 1103–8. http://dx.doi.org/10.1128/cdli.10.6.1103-1108.2003.
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ABSTRACT Secretory immunity protects against mucosal transmission of viruses, as demonstrated with the oral poliovirus vaccine. In a previous study we showed that this immunity could be induced in mice by injection of a fusion peptide consisting of an unnatural peptide-like sequence (PADRE) and a viral epitope (ELDKWASLW). PADRE is a T-helper-cell epitope able to bind most major histocompatibility complex class II molecules of different haplotypes in mice and humans and to increase antibody responses. ELDKWA is a well-known consensual sequence of gp41 involved in a key structure of human immunodeficiency virus (HIV) type 1. Here, the antibody response to the native form of ELDKWA was mainly of the immunoglobulin A isotype and selectively occurred in mucosa. Adjuvants, such as cholera toxin and cytosine polyguanine, were useless and even competed with PADRE for the response. Interestingly, these antibodies were cross-reactive with the three major variants of the epitope, as shown both by direct enzyme-linked immunosorbent assay and by inhibition. This unconventional route of mucosal immunization allows control of the administered dose. The lack of adjuvant and the cross-reactivity of the antibodies increase the safety and the spectrum of the candidate vaccine, respectively. The drug-like nature of the construct suggests further improvements by synthesis of more antigenic sequences. The reasonable cost of short peptides at the industrial level and their purity make this approach of interest for future vaccines against mucosal transmission of HIV or other pathogens.
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Stone, Geoffrey W., Suzanne Barzee, Victoria Snarsky, Celsa A. Spina, Jeffrey D. Lifson, Vinod Kumar Bhaskara Pillai, Rama Rao Amara, François Villinger, and Richard S. Kornbluth. "Macaque Multimeric Soluble CD40 Ligand and GITR Ligand Constructs Are Immunostimulatory Molecules In Vitro." Clinical and Vaccine Immunology 13, no. 11 (September 20, 2006): 1223–30. http://dx.doi.org/10.1128/cvi.00198-06.
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ABSTRACT CD40 ligand (CD40L) and GITR ligand (glucocorticoid-induced tumor necrosis factor receptor-related protein ligand [GITRL]) are tumor necrosis factor superfamily molecules that can be used as vaccine adjuvants. In a previous human immunodeficiency virus (HIV) DNA vaccine study in mice, we found that plasmids expressing multimeric soluble forms of trimeric CD40L (i.e., many trimers) were stronger activators of CD8+ T-cell responses than were single-trimer soluble forms or the natural membrane-bound molecule. This report describes similar multimeric soluble molecules that were constructed for studies in macaques. Both two-trimer and four-trimer forms of macaque CD40L were active in B-cell proliferation assays using macaque and human cells. With human cells, four-trimer macaque GITRL costimulated CD4+ T-cell proliferation and abrogated the immunosuppressive effects of CD4+ CD25+ regulatory T cells on a mixed leukocyte reaction. These molecular adjuvants provide new tools for vaccine development in the simian immunodeficiency virus system and other macaque models.
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Courtney, Amy N., Prakash Thapa, Pramod N. Nehete, Chun Li, Dapeng Zhou, and K. Jagannadha Sastry. "α-GalCer is an effective mucosal adjuvant for repeated nasal or oral delivery of HIV peptide antigens (39.54)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 39.54. http://dx.doi.org/10.4049/jimmunol.182.supp.39.54.
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Abstract Mucosal vaccine delivery is important for strong immune responses at biologically relevant sites, however weakly immunogenic antigens delivered by the mucosal route may induce tolerance. Therefore, appropriate adjuvants should be included for effective mucosal immunization. Mice were immunized by the oral or nasal route with alpha-Galactosylceramide (α-GalCer) as an adjuvant for co-administering with a CTL-inducing HIV envelope peptide (R15K). We observed antigen-specific cellular immune responses in multiple systemic and mucosal tissues. Contrary to the known potential of repeated parenteral dosing with α-GalCer to induce NKT cell anergy that could compromise adoptive immunity, we observed that multiple doses delivered by mucosal routes were more efficient in priming broader antigen-specific immune responses. We also obtained results showing that poly-lactic acid based nanoparticles conjugated with α-GalCer can repeatedly stimulate NKT cells both in vitro and in vivo without inducing anergy. Mechanistic studies showed that nanoparticle-formulated α-GalCer is efficiently presented by mouse CD11c+ dendritic cells and CD11b+ macrophages, but very poorly by B220+ B cells. These results demonstrate the effectiveness of α-GalCer as an adjuvant for repeated administration of vaccines for protection against mucosally transmitted pathogens.
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Leroy, Laury-Anne, Alice Mac Donald, Aditi Kandlur, Deepanwita Bose, Peng Xiao, Jean Gagnon, François Villinger, and Yahia Chebloune. "Cytokine Adjuvants IL-7 and IL-15 Improve Humoral Responses of a SHIV LentiDNA Vaccine in Animal Models." Vaccines 10, no. 3 (March 17, 2022): 461. http://dx.doi.org/10.3390/vaccines10030461.
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HIV-1 remains a major public health issue worldwide in spite of efficacious antiviral therapies, but with no cure or preventive vaccine. The latter has been very challenging, as virus infection is associated with numerous escape mechanisms from host specific immunity and the correlates of protection remain incompletely understood. We have developed an innovative vaccine strategy, inspired by the efficacy of live-attenuated virus, but with the safety of a DNA vaccine, to confer both cellular and humoral responses. The CAL-SHIV-IN− lentiDNA vaccine comprises the backbone of the pathogenic SHIVKU2 genome, able to mimic the early phase of viral infection, but with a deleted integrase gene to ensure safety precluding integration within the host genome. This vaccine prototype, constitutively expressing viral antigen under the CAEV LTR promoter, elicited a variety of vaccine-specific, persistent CD4 and CD8 T cells against SIV-Gag and Nef up to 80 weeks post-immunization in cynomolgus macaques. Furthermore, these specific responses led to antiviral control of the pathogenic SIVmac251. To further improve the efficacy of this vaccine, we incorporated the IL-7 or IL-15 genes into the CAL-SHIV-IN− plasmid DNA in efforts to increase the pool of vaccine-specific memory T cells. In this study, we examined the immunogenicity of the two co-injected lentiDNA vaccines CAL-SHIV-IN− IRES IL-7 and CAL-SHIV-IN− IRES IL-15 in BALB/cJ mice and rhesus macaques and compared the immune responses with those generated by the parental vaccine CAL-SHIV-IN−. This co-immunization elicited potent vaccine-specific CD4 and CD8 T cells both in mice and rhesus macaques. Antibody-dependent cell-mediated cytotoxicity (ADCC) antibodies were detected up to 40 weeks post-immunization in both plasma and mucosal compartments of rhesus macaques and were enhanced by the cytokines.
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Chapman, Rosamund, and Edward P. Rybicki. "Use of a Novel Enhanced DNA Vaccine Vector for Preclinical Virus Vaccine Investigation." Vaccines 7, no. 2 (June 13, 2019): 50. http://dx.doi.org/10.3390/vaccines7020050.
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DNA vaccines are stable, safe, and cost effective to produce and relatively quick and easy to manufacture. However, to date, DNA vaccines have shown relatively poor immunogenicity in humans despite promising preclinical results. Consequently, a number of different approaches have been investigated to improve the immunogenicity of DNA vaccines. These include the use of improved delivery methods, adjuvants, stronger promoters and enhancer elements to increase antigen expression, and codon optimization of the gene of interest. This review describes the creation and use of a DNA vaccine vector containing a porcine circovirus (PCV-1) enhancer element that significantly increases recombinant antigen expression and immunogenicity and allows for dose sparing. A 172 bp region containing the PCV-1 capsid protein promoter (Pcap) and a smaller element (PC; 70 bp) within this were found to be equally effective. DNA vaccines containing the Pcap region expressing various HIV-1 antigens were found to be highly immunogenic in mice, rabbits, and macaques at 4–10-fold lower doses than normally used and to be highly effective in heterologous prime-boost regimens. By lowering the amount of DNA used for immunization, safety concerns over injecting large amounts of DNA into humans can be overcome.
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Costiniuk, Cecilia T., Joel Singer, Marc-André Langlois, Iva Kulic, Judy Needham, Ann Burchell, Mohammad-Ali Jenabian, et al. "CTN 328: immunogenicity outcomes in people living with HIV in Canada following vaccination for COVID-19 (HIV-COV): protocol for an observational cohort study." BMJ Open 11, no. 12 (December 2021): e054208. http://dx.doi.org/10.1136/bmjopen-2021-054208.
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IntroductionMost existing vaccines require higher or additional doses or adjuvants to provide similar protection for people living with HIV (PLWH) compared with HIV-uninfected individuals. Additional research is necessary to inform COVID-19 vaccine use in PLWH.Methods and analysisThis multicentred observational Canadian cohort study will enrol 400 PLWH aged >16 years from Montreal, Ottawa, Toronto and Vancouver. Subpopulations of PLWH of interest will include individuals: (1) >55 years of age; (2) with CD4 counts <350 cells/mm3; (3) with multimorbidity (>2 comorbidities) and (4) ‘stable’ or ‘reference’ PLWH (CD4 T cells >350 cells/mm3, suppressed viral load for >6 months and <1 comorbidity). Data for 1000 HIV-negative controls will be obtained via a parallel cohort study (Stop the Spread Ottawa), using similar time points and methods. Participants receiving >1 COVID-19 vaccine will attend five visits: prevaccination; 1 month following the first vaccine dose; and at 3, 6 and 12 months following the second vaccine dose. The primary end point will be the percentage of PLWH with COVID-19-specific antibodies at 6 months following the second vaccine dose. Humoral and cell-mediated immune responses, and the interplay between T cell phenotypes and inflammatory markers, will be described. Regression techniques will be used to compare COVID-19-specific immune responses to determine whether there are differences between the ‘unstable’ PLWH group (CD4 <350 cells/mm3), the stable PLWH cohort and the HIV-negative controls, adjusting for factors believed to be associated with immune response. Unadjusted analyses will reveal whether there are differences in driving factors associated with group membership.Ethics and disseminationResearch ethics boards at all participating institutions have granted ethics approval for this study. Written informed consent will be obtained from all study participants prior to enrolment. The findings will inform the design of future COVID-19 clinical trials, dosing strategies aimed to improve immune responses and guideline development for PLWH.Trial registration numberNCT04894448.
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Danilenko, V. N. "Development of a technological platfom for creating innovative anti-tb drugs effective against multi-drug-resistant strains." Вестник Российской академии наук 89, no. 5 (May 6, 2019): 427–35. http://dx.doi.org/10.31857/s0869-5873895427-435.
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This article tackles the issue of the growing morbidity and mortality caused by multi-drug-resistant (extreme drug-resistant) tuberculosis (TB). This issue is aggravated by the alarming rise of immunocompromized patients and immigration worldwide. In order to solve this problem, an interdisciplinary approach is needed. Here we offer to: (1) develop innovative diagnostic techniques for identifying dangerous lineages of TB with mutations and drug resistance genes; (2) develop antibiotics with new modes of action effective against multiple drug resistance and extreme drug-resistant strains of TB and HIV; (3) develop new genetically engineered vaccines; and, (4) develop new vaccine adjuvants based on probiotic Lactobacillus and Bifidobacterium stains, with selective immunomodulatory activity.
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Boopathy, Archana Vidya, Anasuya Mandal, Dan W. Kulp, Sudha Kumari, Wade Wang, Yanpu He, Talar Tokatlian, William R. Schief, Paula T. Hammond, and Darrell J. Irvine. "Sustained delivery of a HIV subunit vaccine using silk microneedle skin patches." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 225.22. http://dx.doi.org/10.4049/jimmunol.198.supp.225.22.
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Abstract Many broadly neutralizing antibodies (bNAbs) against HIV exhibit high degrees of somatic hypermutation, suggesting that immunization approaches promoting germinal center (GC) stimulation and affinity maturation may be critical for an HIV vaccine. To this end, we recently demonstrated that sustained exposure of draining lymph nodes (LNs) to env immunogens through repeated injections over 2 weeks enhanced env capture on follicular dendritic cell networks in LNs, with Tfh expansion and GC induction. To obtain similar sustained vaccine kinetics for mass immunization, we developed a submicron-scale dissolving silk microneedle array (MN) for dermal vaccine delivery. We utilized silk protein to encapsulate an HIV envelope trimer (BG505 SOSIP variants) with adjuvants supported by a poly acrylic acid (PAA) base. Upon dermal application, rapid PAA dissolution is followed by silk beta sheet-dependent sustained release of encapsulated vaccine with minimal local inflammation. Antigenicity of SOSIP was maintained in silk as determined by binding to structure-sensitive bNAbs- PGT151, PGT145, PGT121 and VRCO1 without binding to non-bNAb 14e. Following immunization in mice, skin and draining LNs were subjected to lipid clearance using organic solvents and imaged by confocal microscopy. We observed SOSIP and silk co-retention at the skin site of microneedle application after one week. MN delivery resulted in higher SOSIP retention and increased SOSIP-specific T follicular helper cells in the GCs of vaccine draining LNs on day 14 post prime, and increased anti-SOSIP IgG titers on day 28 post prime compared to intradermal injections. Taken together, these results suggest the potential of silk MNs in modulating release of HIV subunit vaccine.
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de Jong, Wesley, Lorna Leal, Jozefien Buyze, Pieter Pannus, Alberto Guardo, Maria Salgado, Beatriz Mothe, et al. "Therapeutic Vaccine in Chronically HIV-1-Infected Patients: A Randomized, Double-Blind, Placebo-Controlled Phase IIa Trial with HTI-TriMix." Vaccines 7, no. 4 (December 6, 2019): 209. http://dx.doi.org/10.3390/vaccines7040209.
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Therapeutic vaccinations aim to re-educate human immunodeficiency virus (HIV)-1-specific immune responses to achieve durable control of HIV-1 replication in virally suppressed infected individuals after antiretroviral therapy (ART) is interrupted. In a double blinded, placebo-controlled phase IIa multicenter study, we investigated the safety and immunogenicity of intranodal administration of the HIVACAT T cell Immunogen (HTI)-TriMix vaccine. It consists of naked mRNA based on cytotoxic T lymphocyte (CTL) targets of subdominant and conserved HIV-1 regions (HTI), in combination with mRNAs encoding constitutively active TLR4, the ligand for CD40 and CD70 as adjuvants (TriMix). We recruited HIV-1-infected individuals under stable ART. Study-arms HTI-TriMix, TriMix or Water for Injection were assigned in an 8:3:3 ratio. Participants received three vaccinations at weeks 0, 2, and 4 in an inguinal lymph node. Two weeks after the last vaccination, immunogenicity was evaluated using ELISpot assay. ART was interrupted at week 6 to study the effect of the vaccine on viral rebound. The vaccine was considered safe and well tolerated. Eighteen percent (n = 37) of the AEs were considered definitely related to the study product (grade 1 or 2). Three SAEs occurred: two were unrelated to the study product, and one was possibly related to ART interruption (ATI). ELISpot assays to detect T cell responses using peptides covering the HTI sequence showed no significant differences in immunogenicity between groups. There were no significant differences in viral load rebound dynamics after ATI between groups. The vaccine was safe and well tolerated. We were not able to demonstrate immunogenic effects of the vaccine.
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Greslehner, Gregor P. "The vaccinologist’s “dirty little secret”: a better understanding of structure-function relationships of viral immunogens might advance rational HIV vaccine design." Archives of Virology 166, no. 5 (February 19, 2021): 1297–303. http://dx.doi.org/10.1007/s00705-021-04982-7.
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AbstractI will offer a conceptual analysis of different notions of structure and function of viral immunogens and of different structure-function relationships. My focus will then be on the mechanisms by which the desired immune response is induced and why strategies based on three-dimensional molecular antigen structures and their rational design are limited in their ability to induce the desired immunogenicity. I will look at the mechanisms of action of adjuvants (thus the wordplay with Janeway’s “immunologist’s dirty little secret”). Strategies involving adjuvants and other (more successful) vaccination strategies rely on taking into account activities and functions (“what is going on”), and not just the structures involved (“who is there”), in binding in a “lock and key” fashion. Functional patterns as well as other organizational and temporal patterns, I will argue, are crucial for inducing the desired immune response and immunogenicity. The 3D structural approach by itself has its benefits – and its limits, which I want to highlight by this philosophical analysis, pointing out the importance of structure-function relationships. Different functional aspects such as antigenicity, immunogenicity, and immunity need to be kept separate and cannot be reduced to three-dimensional structures of vaccines. Taking into account different notions of structure and function and their relationships might thus advance our understanding of the immune system and rational HIV vaccine design, to which end philosophy can provide useful tools.
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Li, Y., K. Svehla, N. L. Mathy, G. Voss, J. R. Mascola, and R. Wyatt. "Characterization of Antibody Responses Elicited by Human Immunodeficiency Virus Type 1 Primary Isolate Trimeric and Monomeric Envelope Glycoproteins in Selected Adjuvants." Journal of Virology 80, no. 3 (February 1, 2006): 1414–26. http://dx.doi.org/10.1128/jvi.80.3.1414-1426.2006.
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ABSTRACT We previously reported that soluble, stable YU2 gp140 trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein immunogens could elicit improved breadth of neutralization against HIV-1 isolates compared to monomeric YU2 gp120 proteins. In this guinea pig immunization study, we sought to extend these data and determine if adjuvant could quantitatively or qualitatively alter the neutralizing response elicited by trimeric or monomeric immunogens. Consistent with our earlier studies, the YU2 gp140 immunogens elicited higher-titer neutralizing antibodies against homologous and heterologous isolates than those elicited by monomeric YU2 gp120. Additionally, the GlaxoSmithKline family of adjuvants AS01B, AS02A, and AS03 induced higher levels of neutralizing antibodies compared to emulsification of the same immunogens in Ribi adjuvant. Further analysis of vaccine sera indicated that homologous virus neutralization was not mediated by antibodies to the V3 loop, although V3 loop-directed neutralization could be detected for some heterologous isolates. In most gp120-inoculated animals, the homologous YU2 neutralization activity was inhibited by a peptide derived from the YU2 V1 loop, whereas the neutralizing activity elicited by YU2 gp140 trimers was much less sensitive to V1 peptide inhibition. Consistent with a less V1-focused antibody response, sera from the gp140-immunized animals more efficiently neutralized heterologous HIV-1 isolates, as determined by two distinct neutralization formats. Thus, there appear to be qualitative differences in the neutralizing antibody response elicited by YU2 gp140 compared to YU2 monomeric gp120. Further mapping analysis of more conserved regions of gp120/gp41 may be required to determine the neutralizing specificity elicited by the trimeric immunogens.
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Reale, Marcella, Claudio Ucciferri, Erica Costantini, Marta Di Nicola, Annamaria Porreca, Pamela Di Giovanni, Michela Pontolillo, Antonio Auricchio, Jacopo Vecchiet, and Katia Falasca. "Effects of Probiotic Mixture Supplementation on the Immune Response to the 13-Valent Pneumococcal Conjugate Vaccine in People Living with HIV." Nutrients 13, no. 12 (December 9, 2021): 4412. http://dx.doi.org/10.3390/nu13124412.
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Background: In people living with HIV, combination antiretroviral therapy (cART) reduces the risk of death, but the persistent immune-deficient state predisposes them to pneumococcal infections. Current guidelines encourage administering pneumococcal vaccine Prevenar 13 to patients living with HIV. Since probiotic supplementation could act as adjuvants and improve vaccine immunogenicity by modulating gut microbiota, the present study aimed to assess whether the effect of a formulation containing a combination of specific probiotics (Vivomixx®) could improve the immune response to 13-valent pneumococcal conjugate vaccine (PCV13) in adult people living with HIV. Methods: Thirty patients who were clinically stable and virologically suppressed, without opportunistic infections during this time and no ART changes in the 12 months before the study started were enrolled. Patients were divided into two groups: (1) received a placebo dose and (2) received Vivomixx® (1800 billion CFU) for four weeks before and after the vaccination with a single dose of PCV13. Results: Vivomixx® supplementation induced a better response to PCV13 immunization, as shown by greater change in anti-Pn CPS13 IgG and increase in salivary IgA, IL-10 and IL-8. Conclusions: Additional investigations will help to clearly and fully elucidate the optimal strains, doses, and timing of administration of probiotics to improve protection upon vaccination in immunocompromised individuals and the elderly.
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Layton, G. T., S. J. Harris, A. J. Gearing, M. Hill-Perkins, J. S. Cole, J. C. Griffiths, N. R. Burns, A. J. Kingsman, and S. E. Adams. "Induction of HIV-specific cytotoxic T lymphocytes in vivo with hybrid HIV-1 V3:Ty-virus-like particles." Journal of Immunology 151, no. 2 (July 15, 1993): 1097–107. http://dx.doi.org/10.4049/jimmunol.151.2.1097.
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Abstract In general, it has proven difficult to induce CTL responses using simple proteins or peptides without resorting to specialized adjuvants. In this study we show that particulate polymeric Ag in the form of hybrid Ty virus-like particles carrying the V3 region of HIV-1 gp120/160 envelope protein (V3:Ty-VLP) induce V3-specific CTL in BALB/c mice in the absence of adjuvant or lipid vehicle. In vitro restimulation of splenocytes with V3 peptide was necessary in order to generate effector CTL. Th cell activation was not required for this in vitro restimulation phase. The CTL induced by the V3:Ty-VLP were CD8+ve, H-2d-restricted, and HIV-1 isolate-specific (IIIB or MN). Co-administration of IIIB V3:Ty-VLP and MN V3:Ty-VLP primed both IIIB and MN V3-specific CTL. However, only IIIB V3-specific CTL were primed by hybrid Ty-VLP carrying IIIB, MN, and RF V3 loop sequences on the same particle indicating that there is intra- but not intermolecular competition between CTL epitopes. In direct comparisons, V3:Ty-VLP were substantially more potent than rgp120. Rgp160 and a 40mer IIIB V3 peptide both failed to prime V3-specific CTL. These data suggest that the particulate nature of hybrid Ty-VLP facilitates uptake into APC with subsequent access to the MHC class I processing pathway and that they may be useful vaccine vehicles for inducing cytolytic immunity against HIV-1 and other intracellular pathogens.
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Mooij, Petra, Sunita S. Balla-Jhagjhoorsingh, Niels Beenhakker, Patricia van Haaften, Ilona Baak, Ivonne G. Nieuwenhuis, Shirin Heidari, et al. "Comparison of Human and Rhesus Macaque T-Cell Responses Elicited by Boosting with NYVAC Encoding Human Immunodeficiency Virus Type 1 Clade C Immunogens." Journal of Virology 83, no. 11 (March 25, 2009): 5881–89. http://dx.doi.org/10.1128/jvi.02345-08.
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ABSTRACT Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-γ) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4+ and CD8+ T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-γ, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-γ T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved.
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AbdelAllah, Nourhan H., Nourtan F. Abdeltawab, Abeer A. Boseila, and Magdy A. Amin. "Chitosan and Sodium Alginate Combinations Are Alternative, Efficient, and Safe Natural Adjuvant Systems for Hepatitis B Vaccine in Mouse Model." Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/7659684.
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Hepatitis B viral (HBV) infections represent major public health problem and are an occupational hazard for healthcare workers. Current alum-adjuvanted HBV vaccine is the most effective measure to prevent HBV infection. However, the vaccine has some limitations including poor response in some vaccinee and being a frost-sensitive suspension. The goal of our study was to use an alternative natural adjuvant system strongly immunogenic allowing for a reduction in dose and cost. We tested HBV surface antigen (HBsAg) adjuvanted with chitosan (Ch) and sodium alginate (S), both natural adjuvants, either alone or combined with alum in mouse model. Mice groups were immunized subcutaneously with HBsAg adjuvanted with Ch or S, or triple adjuvant formula with alum (Al), Ch, and S, or double formulations with AlCh or AlS. These were compared to control groups immunized with current vaccine formula or unadjuvanted HBsAg. We evaluated the rate of seroconversion, serum HBsAg antibody, IL-4, and IFN-γlevels. The results showed that the solution formula with Ch or S exhibited comparable immunogenic responses to Al-adjuvanted suspension. The AlChS gave significantly higher immunogenic response compared to controls. Collectively, our results indicated that Ch and S are effective HBV adjuvants offering natural alternatives, potentially reducing dose.
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Kim, Jong J., Kenneth A. Simbiri, Jeong I. Sin, Kesen Dang, Jim Oh, Tzvete Dentchev, Daniel Lee, et al. "Cytokine Molecular Adjuvants Modulate Immune Responses Induced by DNA Vaccine Constructs for HIV-1 and SIV." Journal of Interferon & Cytokine Research 19, no. 1 (January 1999): 77–84. http://dx.doi.org/10.1089/107999099314441.
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Tom, Janine, Tyler Albin, Amanda M. Burkhardt, Philip Felgner, and Aaron Esser-Kahn. "Development of a tri-agonist compound library used to determine optimal adjuvanticity of a Q fever vaccine." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 76.18. http://dx.doi.org/10.4049/jimmunol.196.supp.76.18.
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Abstract Vaccines are one of the most successful treatments for disease. However, the development of more effective vaccines is still necessary for diseases, such as malaria and HIV. Recently, researchers have demonstrated that administering a target antigen with multiple immune agonists, especially Toll-like receptor (TLR) agonists, can enhance specific immune responses. Thus, suggesting that vaccines will require synergistic activity of multiple agonists to effectively activate the immune system and eliminate disease. In addition, vaccine development would greatly benefit from understanding the effect distinct combinations of immune agonists have on immune activity. This information would allow us to more rationally design vaccines that elicit directed and prolonged immune responses. Previously, we probed immune system responses by conjugating three TLR agonists together. Testing our construct in vitro and in vivo, we were able to modulate innate immune and antibody responses, suggesting downstream changes in immune signaling and adaptive immune activation. Here, we synthesized a library of tri-agonist compounds and examined how different covalently linked TLR agonist combinations affected immune activation via NF-kB activity and cytokine production. We are currently testing our constructs on a Q fever vaccination model, where Q fever is a current bioterrorism threat, to examine changes in T and B cell populations, antibody responses, and efficacy of the tri-agonist adjuvants. From our studies, these tri-agonist scaffolds can inform us about immune system signaling and activation in order to study immune activation mechanisms. Therefore, allowing us to potentially design more effective vaccines.
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Kanagavelu, Saravana K., Victoria Snarsky, James M. Termini, Sachin Gupta, Suzanne Barzee, Jacqueline A. Wright, Wasif N. Khan, Richard S. Kornbluth, and Geoffrey W. Stone. "Soluble multi-trimeric TNF superfamily ligand adjuvants enhance immune responses to a HIV-1 Gag DNA vaccine." Vaccine 30, no. 4 (January 2012): 691–702. http://dx.doi.org/10.1016/j.vaccine.2011.11.088.
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Cheng, Liang, Zheng Zhang, Sandra Zurawski, Gerard Zurawski, Yves Levy, and Lishan Su. "Toll-like receptor ligands differentially activate human innate immune system and distinctively enhance antigen-specific T cell response to vaccination in humanized mice (VAC4P.1105)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 72.10. http://dx.doi.org/10.4049/jimmunol.194.supp.72.10.
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Abstract TLR-Ls represent a new class of novel vaccine adjuvant. However, their immunologic effects in humans remain poorly defined in vivo. Here we investigated how TLR-Ls stimulated human immune system in vivo and their application as immune adjuvant using the humanized mouse model. To our surprise, we found that various TLR-Ls (CpG-A/CpG-B/CpG-C, R848, R837, MPLA and Poly I:C) stimulated human cytokines very differently in humanized mice in vivo compared to that in human PBMCs in vitro. The different in vivo response to TLR-Ls was not due to the improper development of human immune cells in vivo because splenocytes from humanized mice showed identical responses as human PBMC in vitro to various TLR-Ls. Importantly, the human innate immune response to specific TLR-Ls in humanized mice in vivo was different from that reported in C57/BL6 mice, but similar to that reported in nonhuman primates. Furthermore, we showed that distinct TLR-Ls differentially activated and mobilized human pDCs, mDCs and monocytes in different organs in vivo. Finally, we showed that Poly I:C and R848 were superior to CpG-B, for enhancing antigen specific CD4+ and CD8+ T cell responses to a CD40-targeting HIV candidate vaccine in humanized mice, which correlated with their ability to activate human CD141+ mDCs and IL-12 induction. Thus, we conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans.
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Lamrayah, Myriam, Capucine Phelip, Céline Coiffier, Céline Lacroix, Thibaut Willemin, Thomas Trimaille, and Bernard Verrier. "A Polylactide-Based Micellar Adjuvant Improves the Intensity and Quality of Immune Response." Pharmaceutics 14, no. 1 (January 3, 2022): 107. http://dx.doi.org/10.3390/pharmaceutics14010107.
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Micelles from amphiphilic polylactide-block-poly(N-acryloxysuccinimide-co-N-vinylpyrrolidone) (PLA-b-P(NAS-co-NVP)) block copolymers of 105 nm in size were characterized and evaluated in a vaccine context. The micelles were non-toxic in vitro (both in dendritic cells and HeLa cells). In vitro fluorescence experiments combined with in vivo fluorescence tomography imaging, through micelle loading with the DiR near infrared probe, suggested an efficient uptake of the micelles by the immune cells. The antigenic protein p24 of the HIV-1 was successfully coupled on the micelles using the reactive N-succinimidyl ester groups on the micelle corona, as shown by SDS-PAGE analyses. The antigenicity of the coupled antigen was preserved and even improved, as assessed by the immuno-enzymatic (ELISA) test. Then, the performances of the micelles in immunization were investigated and compared to different p24-coated PLA nanoparticles, as well as Alum and MF59 gold standards, following a standardized HIV-1 immunization protocol in mice. The humoral response intensity (IgG titers) was substantially similar between the PLA micelles and all other adjuvants over an extended time range (one year). More interestingly, this immune response induced by PLA micelles was qualitatively higher than the gold standards and PLA nanoparticles analogs, expressed through an increasing avidity index over time (>60% at day 365). Taken together, these results demonstrate the potential of such small-sized micellar systems for vaccine delivery.