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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]
For microbiologic aspects of the causative organism(s), see Human Immunodeficiency Virus (HIV)
For clinical aspects of this desease, see HIV

Overview

HIV infection is a major global health issue, affecting 36.7 million people worldwide. The number of people living with HIV on antiretroviral therapy (ART) reached 17 million in 2015. Although ART has dramatically reduced morbidity and mortality in individuals with HIV infection and can also prevent HIV transmission but it cannot eradicate HIV infection due to the persistence of a latent viral reservoir, hence the need for antiretroviral therapy ART is lifelong and the cost is substantial. Although antiretroviral therapy ART is highly efficacious in preventing transmission in the setting of mother to child transmission, in sexual transmission through the treatment of infected partners in relationships, through pre-exposure or or post-exposure prophylaxis, but all these scale-up difficulties and costs may make widespread implementation challenging. Thus an HIV vaccine is essential as it is a more sustainable solution.The development of a universal effective HIV vaccine is an exceptionally difficult biomedical challenge. Firstly, no case of natural eradication of HIV infection has been identified, thus mechanisms of protection have not been definitively established. Secondly, the extreme diversity of HIV is a major obstacle as strains belonging to different subtypes can differ by up to 35% in their envelope (Env) proteins.Thus, vaccine immunogens derived from a particular strain may not be effective against other strain. To generate an efficacious global vaccine, immunogens capable of generating protective responses covering most major strains are required.

Historical Perspective

  • Ever since HIV was formally identified as the cause of AIDS, there have been ongoing efforts on vaccines against the disease.
  • On April 24, 1984, the US Secretary of Health and Human Services, Margaret Heckler, announced that vaccines will be researched and made ready for preliminary testing by the year 1986.[1]
  • Traditional approaches of using live attenuated or whole inactivated viruses were considered unsafe because of the risk of permanently integrating proviral DNA within host chromosomes.[2]
  • Advancements in vaccine development had to wait until mid-1980's when recombinant DNA technologies were becoming available for research applications.
  • Following the success of recombinant Hepatitis B vaccine, recombinant DNA technologies were also being researched for HIV vaccines.[3]
  • All these efforts came to a standstill with growing knowledge about extreme mutability and immune evasion mechanisms of existing HIV strains.[4]
  • It was further complicated by the fact that neutralizing antibodies had no protective effects and their titers were similar among asymptomatic carriers and patients with active disease. [5]

Clinical trials for HIV vaccine

The 6 HIV-1 vaccine efficacy trials done to date, to delineate potential protective responses, and to explore new vaccine candidates that are currently being developed are as follows.

VAX003 and 004

  • VAX003 was a double-blind, randomized trial of AIDSVAX® B/E (a bivalent vaccine composed of recombinant gp120 from subtype B, strain MN and subtype CRF01_AE, strain A244) in injection drug users (IDU) in Thailand.[6]
  • VAX004 was a double-blind, randomized trial of AIDSVAX® B/B (a bivalent vaccine composed of subtype B rgp120 from strains MN and GNE8) conducted among men who have sex with men (MSM) and women at high risk for heterosexual transmission of HIV-1 in North America and The Netherlands.[7]
  • Despite the development of anti-glyco-proteins 120 antibody responses, both vaccines did not demonstrate protection.
  • The disappointing results from the VAX003 and VAX004 trials and data supporting the importance of cell mediated immunity in controlling viral replication in rhesus macaques and human elite controllers,attention turned to the use of T-cell vaccines to induce HIV-specific cellular immune responses.[8] [9] [10]

STEP and Phambili studies

  • The STEP study was a double-blind, randomized trial of the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals at high risk of HIV-1 acquisition in the Americas, Caribbean and Australia. [11]
  • The Phambili study was a double-blind, randomized trial designed to evaluate the MRKAd5 HIV-1 gag/pol/nef sub-type B vaccine in individuals in South Africa where HIV clade C is predominant. This study was halted following the Step study's interim analysis and subsequent analysis also found no efficacy.[12]

RV144

  • RV144 was a randomized, double-blind trial that evaluated 4 priming injections of ALVAC-HIV [vCP1521], recombinant canarypox vector expressing HIV-1 Gag and Pro (subtype B LAI strain) and CRF01_AE (subtype E) HIV-1 gp120 (92TH023) linked to the transmembrane anchoring portion of gp41 (LAI) plus 2 booster injections, AIDSVAX® B/E (bivalent HIV-1 gp120 subunit vaccine containing a subtype E Env from strain A244 (CM244) and a subtype B Env from strain MN), co-formulated with alum.[13]
  • The rationale for the prime boost strategy was to induce both cellular and humoral responses.
  • The RV144 trial was the only efficacy trial to date that demonstrated efficacy.[14]

HVTN 505

  • The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, placebo-controlled trial of a prime boost, DNA/rAd5 vaccine consisting of a 6-plasmid DNA vaccine. [15]
  • The vaccine induced both cellular and humoral responses. However, these were not associated with protection.[15]

Conclusions

  • None of the vaccine candidates that have completed efficacy trials to date induced strong broadly neutralizing antibodies (bnAb) responses.
  • CD8+ T cell responses were induced in STEP, Phambili and HVTN505 studies but were not associated with protection.
  • Only one trial, RV144 demonstrated efficacy and protection was associated with functional binding antibodies. However, efficacy was of suboptimal magnitude and was not durable.

Broadly neutralizing antibodies

Passive immunization using broadly neutralizing antibodies

  • The efficacy of broadly neutralizing antibodies as passive immunotherapy has been demonstrated in Rhesus monkey models.
  • A single infusion of broadly neutralizing antibody can prevent infection from a single high-dose Simian/Human Immunodeficiency Virus (SHIV) challenge.[19]
  • The use of broadly neutralizing antibodies as passive immunotherapy in its current form will be challenging to implement widely, due to the production costs, the healthcare infrastructures necessary for infusions and the need for repeated administrations.
  • New research is taking place to explore the introduction of broadly neutralizing antibodies(bnAb) using vectored immunoprophylaxis, where adeno-associated virus (AAV) vectors are used to deliver the genes encoding broadly neutralizing antibodies to muscle tissues, thereby enabling long-term production and systemic distribution. This technique has been shown to protect humanized mice as well as rhesus monkey against high dose intravenous and repeated mucosal challenges.[20]

Eliciting broadly neutralizing antibodies through immunization

  • An immunogen that can elicit broadly neutralizing antibodies (bnAb) responses has still not been identified and the high levels of somatic mutations in bnAb suggest complex maturation pathways.
  • The SOSIP gp140 trimer is a mimic of the natural envelope (Env) trimer, where the gp120-gp41 interactions are stabilized by an intermolecular disulfide bond, and the gp41-gp41 interactions are stabilized by an isoleucine-to-proline substitution at position 559 in the N-terminal heptad repeat region of gp41.[21]
  • Immunization with SOSIP trimers induced neutralizing antibodies in rabbits and to a lesser extent in Rhesus monkeys but broadly neutralizing antibody responses were not generated.[22]

CD4 Binding Site Antibodies

  • The virus entry into targeted cells is dependent on viral attachment to the CD4 receptor and is mediated through binding to a conformational epitope on the trimeric envelop glycoprotein termed the CD4 binding site (CD4bs).[23]
  • Any antibody that is specific to CD4 binding sites can block the entry of virus into the cell.
  • Many such antibodies have now been isolated from human donors, and they share common features, such as heavy chain mimicry of the CD4 receptor.[23]
  • One of first CD4 biniding site antibodies that was isolated from human infected individual that had been living with untreated infection for over 15 years is VRC01.[24]
  • A study demonstrated that VRC01 neutralized 91% of pseudovirions at a half maximal inhibitory concentration (IC50) of <50 μg/ml, and neutralized 72% of primary isolates at an IC50 of <1 μg/ml.[24]

Mosaic vaccine

  • All the HIV-1 vaccines that have progressed to efficacy trials to date have predominantly been regional and clade-specific.
  • The goal of mosaic HIV-1 vaccine is to generate immune responses that cover the diverse spectrum of circulating HIV-1 isolates, potentially resulting in a single vaccine that can be rolled out globally.[25]
  • Mosaic HIV-1 antigens delivered by replication-incompetent Ad26 vectors or DNA prime-recombinant vaccinia boost regimens have been shown to augment both the breadth and depth of antigen-specific T cell responses when compared with consensus or natural sequence HIV-1 antigens in Rhesus monkeys.[26]

T-cell based vaccine concepts

  • Most current vaccine concepts aim at inducing antibody responses in the context of appropriate CD4+ T-cell help, while pure CD8+ T-cell approaches have mostly fallen out of favor. Nevertheless, a couple of promising T-cell focused approaches have been developed over the last years, and are scheduled to move into phase 1 trials in the near future.[27]
  • One immunogen, based on a CMV vector, has consistently led to complete control of virus replication in 50–60% of animals in non-human primate challenge studies.[27]
  • The vector used in these studies was based on attenuated Rhesus CMV; whether these interesting immunological features will translate to clinical trials using a human CMV vector remains to be determined.
  • Recent advances in T cell based vaccines have focused on incorporating the near complete gene sequences of several proteins expressed by the viral strains in HIV controllers. These composite immunogens aim at maximizing the incorporation of variable viral epitopes.[26]
  • In a study among rhesus monkeys, it was observed that the mosaic antigens incorporating several phenotypes of HIV-1 Gag, Pol, and Env antigens administered through replication-incompetent adenovirus serotype 26 vectors markedly increased the depth and breadth of T lymphocyte responses.[26]

Conclusion

  • Developing an HIV vaccine is a challenge due to global HIV-1 diversity and the difficulties in inducing protective antibody responses and cellular immune responses.
  • One of the major hurdles for the HIV vaccine field has been the lack of a fully predictive animal model. New humanized mouse models may provide a unique preclinical framework for testing the induction of broadly neutralizing antibodies.
  • The past few years have seen an explosion in the depth of knowledge and number of new potential approaches to generating an effective HIV vaccine, and each new idea has promising concepts in the pipeline aimed at achieving its goals.

References

  1. ↑ "NEW U.S. REPORT NAMES VIRUS THAT MAY CAUSE AIDS - The New York Times".
  2. ↑ Dowdle W (1986). "The search for an AIDS vaccine". Public Health Rep. 101 (3): 232–3. PMC 1477690. PMID 3012619.
  3. ↑ Fischinger PJ, Robey WG, Koprowski H, Gallo RC, Bolognesi DP (September 1985). "Current status and strategies for vaccines against diseases induced by human T-cell lymphotropic retroviruses (HTLV-I, -II, -III)". Cancer Res. 45 (9 Suppl): 4694s–4699s. PMID 2410115.
  4. ↑ Wong-Staal F, Shaw GM, Hahn BH, Salahuddin SZ, Popovic M, Markham P, Redfield R, Gallo RC (August 1985). "Genomic diversity of human T-lymphotropic virus type III (HTLV-III)". Science. 229 (4715): 759–62. PMID 2992084.
  5. ↑ Cheng-Mayer C, Homsy J, Evans LA, Levy JA (April 1988). "Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization". Proc. Natl. Acad. Sci. U.S.A. 85 (8): 2815–9. PMC 280090. PMID 3357892.
  6. ↑ Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, Hu D, Tappero JW, Choopanya K (December 2006). "Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand". J. Infect. Dis. 194 (12): 1661–71. doi:10.1086/508748. PMID 17109337.
  7. ↑ Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF (March 2005). "Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection". J. Infect. Dis. 191 (5): 654–65. doi:10.1086/428404. PMID 15688278.
  8. ↑ Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L, Kostrikis LG, Zhang L, Perelson AS, Ho DD (March 1999). "Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques". J. Exp. Med. 189 (6): 991–8. PMC 2193038. PMID 10075982.
  9. ↑ Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA (February 1999). "Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes". Science. 283 (5403): 857–60. PMID 9933172.
  10. ↑ Altfeld M, Kalife ET, Qi Y, Streeck H, Lichterfeld M, Johnston MN, Burgett N, Swartz ME, Yang A, Alter G, Yu XG, Meier A, Rockstroh JK, Allen TM, Jessen H, Rosenberg ES, Carrington M, Walker BD (October 2006). "HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1". PLoS Med. 3 (10): e403. doi:10.1371/journal.pmed.0030403. PMC 1626551. PMID 17076553.
  11. ↑ Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D, Gilbert PB, Lama JR, Marmor M, Del Rio C, McElrath MJ, Casimiro DR, Gottesdiener KM, Chodakewitz JA, Corey L, Robertson MN (November 2008). "Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial". Lancet. 372 (9653): 1881–1893. doi:10.1016/S0140-6736(08)61591-3. PMC 2721012. PMID 19012954.
  12. ↑ Gray GE, Allen M, Moodie Z, Churchyard G, Bekker LG, Nchabeleng M, Mlisana K, Metch B, de Bruyn G, Latka MH, Roux S, Mathebula M, Naicker N, Ducar C, Carter DK, Puren A, Eaton N, McElrath MJ, Robertson M, Corey L, Kublin JG (July 2011). "Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study". Lancet Infect Dis. 11 (7): 507–15. doi:10.1016/S1473-3099(11)70098-6. PMC 3417349. PMID 21570355.
  13. ↑ Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH (December 2009). "Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand". N. Engl. J. Med. 361 (23): 2209–20. doi:10.1056/NEJMoa0908492. PMID 19843557.
  14. ↑ Robb ML, Rerks-Ngarm S, Nitayaphan S, Pitisuttithum P, Kaewkungwal J, Kunasol P, Khamboonruang C, Thongcharoen P, Morgan P, Benenson M, Paris RM, Chiu J, Adams E, Francis D, Gurunathan S, Tartaglia J, Gilbert P, Stablein D, Michael NL, Kim JH (July 2012). "Risk behaviour and time as covariates for efficacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144". Lancet Infect Dis. 12 (7): 531–7. doi:10.1016/S1473-3099(12)70088-9. PMC 3530398. PMID 22652344.
  15. ↑ 15.0 15.1 Hammer SM, Sobieszczyk ME, Janes H, Karuna ST, Mulligan MJ, Grove D, Koblin BA, Buchbinder SP, Keefer MC, Tomaras GD, Frahm N, Hural J, Anude C, Graham BS, Enama ME, Adams E, DeJesus E, Novak RM, Frank I, Bentley C, Ramirez S, Fu R, Koup RA, Mascola JR, Nabel GJ, Montefiori DC, Kublin J, McElrath MJ, Corey L, Gilbert PB (November 2013). "Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine". N. Engl. J. Med. 369 (22): 2083–92. doi:10.1056/NEJMoa1310566. PMC 4030634. PMID 24099601.
  16. ↑ Simek MD, Rida W, Priddy FH, Pung P, Carrow E, Laufer DS, Lehrman JK, Boaz M, Tarragona-Fiol T, Miiro G, Birungi J, Pozniak A, McPhee DA, Manigart O, Karita E, Inwoley A, Jaoko W, Dehovitz J, Bekker LG, Pitisuttithum P, Paris R, Walker LM, Poignard P, Wrin T, Fast PE, Burton DR, Koff WC (July 2009). "Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm". J. Virol. 83 (14): 7337–48. doi:10.1128/JVI.00110-09. PMC 2704778. PMID 19439467.
  17. ↑ Doria-Rose NA, Klein RM, Manion MM, O'Dell S, Phogat A, Chakrabarti B, Hallahan CW, Migueles SA, Wrammert J, Ahmed R, Nason M, Wyatt RT, Mascola JR, Connors M (January 2009). "Frequency and phenotype of human immunodeficiency virus envelope-specific B cells from patients with broadly cross-neutralizing antibodies". J. Virol. 83 (1): 188–99. doi:10.1128/JVI.01583-08. PMC 2612342. PMID 18922865.
  18. ↑ Kwong PD, Mascola JR, Nabel GJ (September 2013). "Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning". Nat. Rev. Immunol. 13 (9): 693–701. doi:10.1038/nri3516. PMID 23969737.
  19. ↑ Gautam R, Nishimura Y, Pegu A, Nason MC, Klein F, Gazumyan A, Golijanin J, Buckler-White A, Sadjadpour R, Wang K, Mankoff Z, Schmidt SD, Lifson JD, Mascola JR, Nussenzweig MC, Martin MA (May 2016). "A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges". Nature. 533 (7601): 105–109. doi:10.1038/nature17677. PMC 5127204. PMID 27120156.
  20. ↑ Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, Desrosiers RC, Clark KR (August 2009). "Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys". Nat. Med. 15 (8): 901–6. doi:10.1038/nm.1967. PMC 2723177. PMID 19448633.
  21. ↑ Sanders RW, Vesanen M, Schuelke N, Master A, Schiffner L, Kalyanaraman R, Paluch M, Berkhout B, Maddon PJ, Olson WC, Lu M, Moore JP (September 2002). "Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1". J. Virol. 76 (17): 8875–89. PMC 136973. PMID 12163607.
  22. ↑ Sanders RW, van Gils MJ, Derking R, Sok D, Ketas TJ, Burger JA, Ozorowski G, Cupo A, Simonich C, Goo L, Arendt H, Kim HJ, Lee JH, Pugach P, Williams M, Debnath G, Moldt B, van Breemen MJ, Isik G, Medina-Ramírez M, Back JW, Koff WC, Julien JP, Rakasz EG, Seaman MS, Guttman M, Lee KK, Klasse PJ, LaBranche C, Schief WR, Wilson IA, Overbaugh J, Burton DR, Ward AB, Montefiori DC, Dean H, Moore JP (July 2015). "HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers". Science. 349 (6244): aac4223. doi:10.1126/science.aac4223. PMC 4498988. PMID 26089353.
  23. ↑ 23.0 23.1 Wu X, Wang C, O'Dell S, Li Y, Keele BF, Yang Z, Imamichi H, Doria-Rose N, Hoxie JA, Connors M, Shaw GM, Wyatt RT, Mascola JR (May 2012). "Selection pressure on HIV-1 envelope by broadly neutralizing antibodies to the conserved CD4-binding site". J. Virol. 86 (10): 5844–56. doi:10.1128/JVI.07139-11. PMC 3347292. PMID 22419808.
  24. ↑ 24.0 24.1 Wu X, Yang ZY, Li Y, Hogerkorp CM, Schief WR, Seaman MS, Zhou T, Schmidt SD, Wu L, Xu L, Longo NS, McKee K, O'Dell S, Louder MK, Wycuff DL, Feng Y, Nason M, Doria-Rose N, Connors M, Kwong PD, Roederer M, Wyatt RT, Nabel GJ, Mascola JR (August 2010). "Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1". Science. 329 (5993): 856–61. doi:10.1126/science.1187659. PMC 2965066. PMID 20616233.
  25. ↑ Fischer W, Perkins S, Theiler J, Bhattacharya T, Yusim K, Funkhouser R, Kuiken C, Haynes B, Letvin NL, Walker BD, Hahn BH, Korber BT (January 2007). "Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants". Nat. Med. 13 (1): 100–6. doi:10.1038/nm1461. PMID 17187074.
  26. ↑ 26.0 26.1 26.2 Barouch DH, O'Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun YH, La Porte A, Riggs AM, Lynch DM, Clark SL, Backus K, Perry JR, Seaman MS, Carville A, Mansfield KG, Szinger JJ, Fischer W, Muldoon M, Korber B (March 2010). "Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys". Nat. Med. 16 (3): 319–23. doi:10.1038/nm.2089. PMC 2834868. PMID 20173752.
  27. ↑ 27.0 27.1 Hansen SG, Ford JC, Lewis MS, Ventura AB, Hughes CM, Coyne-Johnson L, Whizin N, Oswald K, Shoemaker R, Swanson T, Legasse AW, Chiuchiolo MJ, Parks CL, Axthelm MK, Nelson JA, Jarvis MA, Piatak M, Lifson JD, Picker LJ (May 2011). "Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine". Nature. 473 (7348): 523–7. doi:10.1038/nature10003. PMC 3102768. PMID 21562493.
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