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'''For microbiologic aspects of the causative organism(s), see''' [[Human Immunodeficiency Virus (HIV)|Human Immunodeficiency Virus (HIV)]] <br> '''For clinical aspects of this desease, see''' [[HIV AIDS|HIV]]
==Overview==
==Overview==
A '''HIV vaccine''' is a hypothetical [[vaccine]] against [[HIV]], the [[etiology|etiological]] agent of [[AIDS]]. As there is no known cure for AIDS, the search for a vaccine has become part of the struggle against the disease.
HIV infection is a major global health issue, affecting 36.7 million people worldwide. The number of people living with HIV on [[AIDS antiretroviral drugs|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 infection|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 [[Vertical transmission|mother to child transmission]], in sexual transmission through the treatment of infected partners in relationships, through [[Pre-exposure prophylaxis|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 [[Viral envelope|envelope]] (Env) proteins.Thus, vaccine immunogens derived from a particular strain may not be effective against other strain. To generate an efficacious global vaccine, [[Antigens|immunogens]] capable of generating protective responses covering most major strains are required.


The urgency of the search for a vaccine against [[HIV]] stems from the AIDS-related death toll of over 25 million people since 1981.<ref name = "AIDSepidemicupdate">{{cite web| format = PDF
==Historical Perspective==
| url = http://www.unaids.org/html/pub/publications/irc-pub06/epi_update2005_en_pdf.pdf
*Ever since HIV was formally identified as the cause of AIDS, there have been ongoing efforts on vaccines against the disease.
| accessdate = 2006-01-20 | title = AIDS epidemic update | publisher = [[World Health Organization]]  
*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.<ref name="urlNEW U.S. REPORT NAMES VIRUS THAT MAY CAUSE AIDS - The New York Times">{{cite web |url=https://www.nytimes.com/1984/04/24/science/new-us-report-names-virus-that-may-cause-aids.html |title=NEW U.S. REPORT NAMES VIRUS THAT MAY CAUSE AIDS - The New York Times |format= |work= |accessdate=}}</ref>
| author = Joint United Nations Programme on HIV/AIDS ([[UNAIDS]]) | year = December 2005 }}</ref> Indeed, in [[2002]], [[AIDS]] became the primary cause of [[death|mortality]] due to an [[infectious agent]] in [[Africa]] ([[UNAIDS]], 2004).  
*Traditional approaches of using [[Attenuated virus|live attenuated]] or whole inactivated viruses were considered unsafe because of the risk of permanently integrating proviral DNA within host [[Chromosomes|chromosomes.]]<ref name="pmid3012619">{{cite journal |vauthors=Dowdle W |title=The search for an AIDS vaccine |journal=Public Health Rep |volume=101 |issue=3 |pages=232–3 |date=1986 |pmid=3012619 |pmc=1477690 |doi= |url=}}</ref>
*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 technology|recombinant DNA technologies]] were also being researched for HIV vaccines.<ref name="pmid2410115">{{cite journal |vauthors=Fischinger PJ, Robey WG, Koprowski H, Gallo RC, Bolognesi DP |title=Current status and strategies for vaccines against diseases induced by human T-cell lymphotropic retroviruses (HTLV-I, -II, -III) |journal=Cancer Res. |volume=45 |issue=9 Suppl |pages=4694s–4699s |date=September 1985 |pmid=2410115 |doi= |url=}}</ref>
*All these efforts came to a standstill with growing knowledge about extreme [[mutability]] and [[Immune system|immune evasion]] mechanisms of existing HIV strains.<ref name="pmid2992084">{{cite journal |vauthors=Wong-Staal F, Shaw GM, Hahn BH, Salahuddin SZ, Popovic M, Markham P, Redfield R, Gallo RC |title=Genomic diversity of human T-lymphotropic virus type III (HTLV-III) |journal=Science |volume=229 |issue=4715 |pages=759–62 |date=August 1985 |pmid=2992084 |doi= |url=}}</ref>
*It was further complicated by the fact that neutralizing antibodies had no protective effects and their [[Titer|titers]] were similar among asymptomatic carriers and patients with active disease. <ref name="pmid3357892">{{cite journal |vauthors=Cheng-Mayer C, Homsy J, Evans LA, Levy JA |title=Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue=8 |pages=2815–9 |date=April 1988 |pmid=3357892 |pmc=280090 |doi= |url=}}</ref>


Alternative medical treatments to a vaccine do exist. [[Highly active antiretroviral therapy]] (HAART) has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.  HAART allows the stabilisation of the patient’s symptoms and viremia, but they do not cure the patient of HIV, nor of the symptoms of AIDS (Martinez-Picardo et al., 2000).  And, importantly, HAART does nothing to prevent the spread of HIV through people with undiagnosed HIV infections. [[Safer sex]] measures have also proven insufficient to halt the spread of AIDS in the worst affected countries, despite some success in reducing infection rates. 
== 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.


Therefore, a HIV vaccine is generally considered as the most likely, perhaps the only way by which the AIDS pandemic can be halted. However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.
===VAX003 and 004===
*VAX003 was a [[Double-blind trial|double-blind]], [[Randomized controlled trial|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.<ref name="pmid17109337">{{cite journal |vauthors=Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, van Griensven F, Hu D, Tappero JW, Choopanya K |title=Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand |journal=J. Infect. Dis. |volume=194 |issue=12 |pages=1661–71 |date=December 2006 |pmid=17109337 |doi=10.1086/508748 |url=}}</ref>
*VAX004 was a [[double-blind]], [[Randomized controlled trial|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.<ref name="pmid15688278">{{cite journal |vauthors=Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF |title=Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection |journal=J. Infect. Dis. |volume=191 |issue=5 |pages=654–65 |date=March 2005 |pmid=15688278 |doi=10.1086/428404 |url=}}</ref>
*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|cell mediated immunity]] in controlling viral replication in [[Rhesus Macaque|rhesus macaques]] and human elite controllers,attention turned to the use of [[T cell|T-cell]] vaccines to induce HIV-specific cellular immune responses.<ref name="pmid10075982">{{cite journal |vauthors=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 |title=Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques |journal=J. Exp. Med. |volume=189 |issue=6 |pages=991–8 |date=March 1999 |pmid=10075982 |pmc=2193038 |doi= |url=}}</ref> <ref name="pmid9933172">{{cite journal |vauthors=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 |title=Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes |journal=Science |volume=283 |issue=5403 |pages=857–60 |date=February 1999 |pmid=9933172 |doi= |url=}}</ref> <ref name="pmid17076553">{{cite journal |vauthors=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 |title=HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1 |journal=PLoS Med. |volume=3 |issue=10 |pages=e403 |date=October 2006 |pmid=17076553 |pmc=1626551 |doi=10.1371/journal.pmed.0030403 |url=}}</ref>
===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. <ref name="pmid19012954">{{cite journal |vauthors=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 |title=Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial |journal=Lancet |volume=372 |issue=9653 |pages=1881–1893 |date=November 2008 |pmid=19012954 |pmc=2721012 |doi=10.1016/S0140-6736(08)61591-3 |url=}}</ref>
*The Phambili study was a [[double-blind]], [[Randomized controlled trial|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.<ref name="pmid21570355">{{cite journal |vauthors=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 |title=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 |journal=Lancet Infect Dis |volume=11 |issue=7 |pages=507–15 |date=July 2011 |pmid=21570355 |pmc=3417349 |doi=10.1016/S1473-3099(11)70098-6 |url=}}</ref>
===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 protein|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.<ref name="pmid19843557">{{cite journal |vauthors=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 |title=Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand |journal=N. Engl. J. Med. |volume=361 |issue=23 |pages=2209–20 |date=December 2009 |pmid=19843557 |doi=10.1056/NEJMoa0908492 |url=}}</ref>
*The rationale for the prime boost strategy was to induce both [[Cellular immunity|cellular]] and [[Humoral immunity|humoral]] responses.
*The RV144 trial was the only efficacy trial to date that demonstrated [[efficacy]].<ref name="pmid22652344">{{cite journal |vauthors=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 |title=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 |journal=Lancet Infect Dis |volume=12 |issue=7 |pages=531–7 |date=July 2012 |pmid=22652344 |pmc=3530398 |doi=10.1016/S1473-3099(12)70088-9 |url=}}</ref>
===HVTN 505===
*The last efficacy trial conducted to date is the HVTN 505 trial, a randomized, [[Placebo-controlled studies|placebo-controlled trial]] of a prime boost, DNA/rAd5 vaccine consisting of a 6-[[plasmid]] DNA vaccine. <ref name="pmid24099601">{{cite journal |vauthors=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 |title=Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine |journal=N. Engl. J. Med. |volume=369 |issue=22 |pages=2083–92 |date=November 2013 |pmid=24099601 |pmc=4030634 |doi=10.1056/NEJMoa1310566 |url=}}</ref>
* The vaccine induced both cellular and [[Humoral immunity|humoral]] responses. However, these were not associated with protection.<ref name="pmid24099601">{{cite journal |vauthors=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 |title=Efficacy trial of a DNA/rAd5 HIV-1 preventive vaccine |journal=N. Engl. J. Med. |volume=369 |issue=22 |pages=2083–92 |date=November 2013 |pmid=24099601 |pmc=4030634 |doi=10.1056/NEJMoa1310566 |url=}}</ref>


==Difficulties in developing an HIV vaccine==
=== Conclusions ===
In 1984, after the confirmation of the etiological agent of AIDS by scientists at the U.S. National Institutes of Health and the [[Pasteur Institute]], the United States Health and Human Services Secretary [[Margaret Heckler]] declared that a [[vaccine]] would be available within two years (Associated Press, 1984). However, the classical vaccination approaches that have been successful in the control of various viral diseases by priming the [[adaptive immunity]] to recognise the viral envelope proteins have failed in the case of HIV-1, as the [[epitope]]s of the viral envelope are too variable. Furthermore, the functionally important epitopes of the gp120 protein are masked by [[glycosylation]], [[trimerisation]] and receptor-induced conformational changes making it difficult to block with neutralising antibodies. In February 2003, [[Vaxgen]] announced that their [[AIDSVAX]] vaccine was a failure in [[North America]] as there was not a statistically significant reduction of HIV infection within the study population (Francis et al., 2003). In November 2003, it also failed clinical trials in [[Thailand]] for the same reason. These vaccines both targeted [[gp120]] and were specific for the geographical regions (Billich et al., 2001).
* 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.


The ineffectiveness of previously developed vaccines primarily stems from two related factors. First, HIV is highly mutable. Because of the virus' ability to rapidly respond to selective pressures imposed by the immune system, the population of virus in an infected individual typically evolves so that it can evade the two major arms of the adaptive immune system; humoral ([[antibody]]-mediated) and systemic (mediated by [[T cells]]) immunity. Second, HIV isolates are themselves highly variable. HIV can be categorized into multiple [[clade]]s and subtypes with a high degree of genetic divergence. Therefore, the immune responses raised by any vaccine need to be broad enough to account for this variability. Any vaccine that lacks this breadth is unlikely to be effective.  
==Broadly neutralizing antibodies==
===Animal model===
*They are [[antibodies]] capable of neutralizing diverse circulating strains from multiple [[clade]] groups, can be present in 20–30% of individuals with HIV-1 [[infection]].<ref name="pmid19439467">{{cite journal |vauthors=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 |title=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 |journal=J. Virol. |volume=83 |issue=14 |pages=7337–48 |date=July 2009 |pmid=19439467 |pmc=2704778 |doi=10.1128/JVI.00110-09 |url=}}</ref>
The typical [[animal model]] for vaccine research is the monkey, often the [[macaque]]. The monkeys can be infected with [[SIV]] or the chimeric [[SHIV]] for research purposes. However, the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates (Poignard et al., 1999). Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge (Berman et al., 1990), but in clinical trials, individuals who were immunised with similar constructs became infected after later exposure to HIV-1 (Connor et al., 1998).  
*They usually develop 2–4 years after HIV-1 infection, in the presence of continual [[antigen]] stimulation from [[viral replication]].<ref name="pmid18922865">{{cite journal |vauthors=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 |title=Frequency and phenotype of human immunodeficiency virus envelope-specific B cells from patients with broadly cross-neutralizing antibodies |journal=J. Virol. |volume=83 |issue=1 |pages=188–99 |date=January 2009 |pmid=18922865 |pmc=2612342 |doi=10.1128/JVI.01583-08 |url=}}</ref>
*HIV [[Viral envelope|envelope]] protein, composed of [[gp120]] and  [[gp41]] [[Monomer|monomers]], is the main target for broadly neutralizing antibodies. <ref name="pmid23969737">{{cite journal |vauthors=Kwong PD, Mascola JR, Nabel GJ |title=Broadly neutralizing antibodies and the search for an HIV-1 vaccine: the end of the beginning |journal=Nat. Rev. Immunol. |volume=13 |issue=9 |pages=693–701 |date=September 2013 |pmid=23969737 |doi=10.1038/nri3516 |url=}}</ref>
===Passive immunization using broadly neutralizing antibodies===
*The [[efficacy]] of broadly neutralizing antibodies as [[Passive immunity|passive]] [[immunotherapy]] has been demonstrated in Rhesus monkey models.
*A single [[Intravenous therapy|infusion]] of broadly neutralizing antibody can prevent infection from a single high-dose Simian/Human Immunodeficiency Virus (SHIV) challenge.<ref name="pmid27120156">{{cite journal |vauthors=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 |title=A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges |journal=Nature |volume=533 |issue=7601 |pages=105–109 |date=May 2016 |pmid=27120156 |pmc=5127204 |doi=10.1038/nature17677 |url=}}</ref>
*The use of broadly neutralizing antibodies as [[Passive immunity|passive]] [[immunotherapy]] in its current form will be challenging to implement widely, due to the production costs, the healthcare infrastructures necessary for [[Intravenous therapy|infusions]] and the need for repeated administrations.
*New research is taking place to explore the introduction of broadly neutralizing antibodies(bnAb) using [[Vector (biology)|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.<ref name="pmid19448633">{{cite journal |vauthors=Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, Desrosiers RC, Clark KR |title=Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys |journal=Nat. Med. |volume=15 |issue=8 |pages=901–6 |date=August 2009 |pmid=19448633 |pmc=2723177 |doi=10.1038/nm.1967 |url=}}</ref>


The human body can defend itself against HIV, as work with monoclonal antibodies (MAb) has proven. That certain individuals can be asymptomatic for decades after infection is encouraging.
===Eliciting broadly neutralizing antibodies through immunization===
*An [[Immunogenicity|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 [[Disulfide bond|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.<ref name="pmid12163607">{{cite journal |vauthors=Sanders RW, Vesanen M, Schuelke N, Master A, Schiffner L, Kalyanaraman R, Paluch M, Berkhout B, Maddon PJ, Olson WC, Lu M, Moore JP |title=Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1 |journal=J. Virol. |volume=76 |issue=17 |pages=8875–89 |date=September 2002 |pmid=12163607 |pmc=136973 |doi= |url=}}</ref>
*[[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.<ref name="pmid26089353">{{cite journal |vauthors=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 |title=HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers |journal=Science |volume=349 |issue=6244 |pages=aac4223 |date=July 2015 |pmid=26089353 |pmc=4498988 |doi=10.1126/science.aac4223 |url=}}</ref>


==Clinical trials to date==
===CD4 Binding Site Antibodies===
*The [[virus]] entry into targeted cells is dependent on viral attachment to the [[CD4+ cell|CD4]] receptor and is mediated through binding to a conformational [[epitope]] on the trimeric [[Viral envelope|envelop]] [[glycoprotein]] termed the [[CD4|CD4 binding site]] (CD4bs).<ref name="pmid22419808">{{cite journal |vauthors=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 |title=Selection pressure on HIV-1 envelope by broadly neutralizing antibodies to the conserved CD4-binding site |journal=J. Virol. |volume=86 |issue=10 |pages=5844–56 |date=May 2012 |pmid=22419808 |pmc=3347292 |doi=10.1128/JVI.07139-11 |url=}}</ref>
*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 chains|heavy chain]] mimicry of the [[CD4|CD4 receptor]].<ref name="pmid22419808">{{cite journal |vauthors=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 |title=Selection pressure on HIV-1 envelope by broadly neutralizing antibodies to the conserved CD4-binding site |journal=J. Virol. |volume=86 |issue=10 |pages=5844–56 |date=May 2012 |pmid=22419808 |pmc=3347292 |doi=10.1128/JVI.07139-11 |url=}}</ref>
*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.<ref name="pmid20616233">{{cite journal |vauthors=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 |title=Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1 |journal=Science |volume=329 |issue=5993 |pages=856–61 |date=August 2010 |pmid=20616233 |pmc=2965066 |doi=10.1126/science.1187659 |url=}}</ref>
*A study demonstrated that VRC01 neutralized 91% of [[pseudovirion]]<nowiki/>s<nowiki/> at a half maximal inhibitory concentration (IC50) of <50 μg/ml, and neutralized 72% of primary isolates at an IC50 of <1 μg/ml.<ref name="pmid20616233">{{cite journal |vauthors=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 |title=Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1 |journal=Science |volume=329 |issue=5993 |pages=856–61 |date=August 2010 |pmid=20616233 |pmc=2965066 |doi=10.1126/science.1187659 |url=}}</ref>
*


Several vaccine candidates are in varying phases of [[clinical trial]]s. 17 vaccine candidates are in [[Clinical trial|phase I trials]] and four in phase I/II. There is only one in phase III (the NIH/Department of Defense’s ALVAC vCP 1521 canary pox vector/AIDSVAX prime-boost vaccine trial now under way in Thailand).
==Mosaic vaccine==
{{update}}
*All the HIV-1 vaccines that have progressed to [[Efficacy|efficacy trials]] to date have predominantly been regional and [[Clade|clade-specific.]]
Up to May 2000 over 60 phase I/II trials of candidate vaccines had been conducted worldwide.
*The goal of [[Mosaic viruses|mosaic]] HIV-1 vaccine is to generate [[Immunity (medical)|immune]] responses that cover the diverse spectrum of circulating HIV-1 isolates, potentially resulting in a single vaccine that can be rolled out globally.<ref name="pmid17187074">{{cite journal |vauthors=Fischer W, Perkins S, Theiler J, Bhattacharya T, Yusim K, Funkhouser R, Kuiken C, Haynes B, Letvin NL, Walker BD, Hahn BH, Korber BT |title=Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants |journal=Nat. Med. |volume=13 |issue=1 |pages=100–6 |date=January 2007 |pmid=17187074 |doi=10.1038/nm1461 |url=}}</ref>
===Phase I===
*Mosaic HIV-1 [[antigens]] delivered by [[Replication-defective virus|replication]]-incompetent Ad26 vectors or DNA prime-[[Recombinant|recombinant vaccinia]] boost regimens have been shown to augment both the breadth and depth of [[Antigen|antigen-specific]] T cell responses when compared with consensus or natural sequence HIV-1 antigens in Rhesus monkeys.<ref name="pmid20173752">{{cite journal |vauthors=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 |title=Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys |journal=Nat. Med. |volume=16 |issue=3 |pages=319–23 |date=March 2010 |pmid=20173752 |pmc=2834868 |doi=10.1038/nm.2089 |url=}}</ref>
Most initial approaches focused on the [[HIV structure and genome|HIV envelope]] protein. At least thirteen different [[gp120]] and [[HIV structure and genome|gp160]] envelope candidates have been evaluated, in the US predominantly through the [[AIDS Vaccine Evaluation Group]]. Most research focused on gp120 rather than gp41/gp160, as the latter are generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced [[Cytotoxic T cell|CD8+ cytotoxic T lymphocytes]] (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. Although the vaccination process involved many repeated "[[booster]]" injections, it was very difficult to induce and maintain the high anti-gp120 antibody [[titer]]s necessary to have any hope of neutralizing an HIV exposure.


The availability of several recombinant [[canarypox]] [[vector (biology)|vectors]] has provided interesting results that may prove to be generalizable to other [[viral vector]]s. Increasing the complexity of the canarypox vectors by inclusion of more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increasing the dose of the viral vector. Importantly, CTLs from volunteers were able to kill [[peripheral blood mononuclear cell]]s infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. In addition, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though the pattern of recognition was not uniform among volunteers. As canarypox is the first candidate HIV vaccine that has induced cross-clade functional CTL responses,
==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 I trial|phase 1 trials]] in the near future.<ref name="pmid21562493">{{cite journal |vauthors=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 |title=Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine |journal=Nature |volume=473 |issue=7348 |pages=523–7 |date=May 2011 |pmid=21562493 |pmc=3102768 |doi=10.1038/nature10003 |url=}}</ref>
*One [[Immunogenicity|immunogen]], based on a [[Cytomegalovirus|CMV]] vector, has consistently led to complete control of virus replication in 50–60% of animals in non-human primate challenge studies.<ref name="pmid21562493">{{cite journal |vauthors=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 |title=Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine |journal=Nature |volume=473 |issue=7348 |pages=523–7 |date=May 2011 |pmid=21562493 |pmc=3102768 |doi=10.1038/nature10003 |url=}}</ref>
*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 [[Epitope|epitopes]].<ref name="pmid20173752">{{cite journal |vauthors=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 |title=Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys |journal=Nat. Med. |volume=16 |issue=3 |pages=319–23 |date=March 2010 |pmid=20173752 |pmc=2834868 |doi=10.1038/nm.2089 |url=}}</ref>
*In a study among rhesus monkeys, it was observed that the [[Mosaic viruses|mosaic]] antigens incorporating several [[Phenotype|phenotypes]] of HIV-1 Gag, Pol, and Env [[Antigen|antigens]] administered through replication-incompetent [[Adenoviridae|adenovirus]] serotype 26 vectors markedly increased the depth and breadth of [[T cell|T lymphocyte]] responses.<ref name="pmid20173752">{{cite journal |vauthors=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 |title=Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys |journal=Nat. Med. |volume=16 |issue=3 |pages=319–23 |date=March 2010 |pmid=20173752 |pmc=2834868 |doi=10.1038/nm.2089 |url=}}</ref>


Other strategies that have progressed to phase I trials in uninfected persons include peptides, [[lipopeptide]]s, [[DNA vaccination|DNA]], an [[attenuation (biology)|attenuated]] [[Salmonella]] vector, lipopeptides, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought:
==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.
* broadly neutralizing [[antibody]] against HIV primary isolates;
*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.
* cytotoxic T cell responses in a vast majority of recipients;
*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.
* strong mucosal [[immune response]]s.
===Phase II===
On [[December 13]] [[2004]], a large phase II clinical trial of a novel HIV vaccine began enrolling volunteers at sites in North America, South America, the Caribbean and Australia. The organizers were seeking 3,000 participants. The trial was co-funded by the [[National Institute of Allergy and Infectious Diseases]] (NIAID), part of the [[National Institutes of Health]] (NIH), and the pharmaceutical company [[Merck & Co.]] Inc. Merck developed the experimental vaccine called V520 to stimulate HIV-specific cellular immunity, which prompts the body to produce T cells that kill HIV-infected cells. In previous smaller trials, this vaccine was found to be safe and to induce cellular immune responses against HIV in more than half of volunteers.<ref name = "AIDSepidemicupdate" />
 
V520 contains a weakened [[adenovirus]] that serves as a carrier for three subtype B HIV genes. Subtype B is the most prevalent HIV subtype in the regions of the study sites. Adenoviruses are among the main causes of upper respiratory tract ailments such as the [[common cold]]. Because the vaccine contains only three HIV genes housed in a weakened adenovirus, study participants cannot become infected with HIV or get a respiratory infection from the vaccine. It was announced in September 2007 that the trial for V520 would be discontinued after it determined that the vaccination was ineffective. [http://ap.google.com/article/ALeqM5gLCTkY4dHmXWHR-SKFi-4GeRDajg]
 
Organizers expected results in 2009, however in September 2007 declared the vaccine a failure. [http://www.nytimes.com/aponline/us/AP-AIDS-Vaccine-Fails.html]
===Phase III===
In February 2003, [[VaxGen]] announced that their [[AIDSVAX]] vaccine was a failure in North America as there was not a statistically significant reduction of HIV infection within the study population. This same vaccine was retested in Thailand within a vaccine regimen called RV 144 beginning in 2003, with positive results.  In both cases the vaccines targeted [[gp120]] and were specific for the geographical regions.  The Thai trial was the largest AIDS vaccine trial to date when it started.<ref name=Harmon2009>{{Cite news
|last=Harmon |first=Katherine |publication-date=January 2010 |date=16 November 2009 |year=2009
|title=Renewed Hope |periodical=[[Scientific American]] |volume=302 |issue=1 |pages=15&ndash;16
|url=http://www.scientificamerican.com/article.cfm?id=renewed-hope-aids-vaccine
|archiveurl=<!--http://www.webcitation.org/5mEyGfWsP--> |archivedate=<!--23 December 2009-->
|accessdate=23 December 2009 |doi=10.1038/scientificamerican0110-15
}}</ref>
 
In October 2009, the results of the RV 144 trial were published. Initial results, released in September 2009 prior to publication of complete results, were encouraging for scientists in search of a vaccine. The study involved 16,395 participants who did not have HIV infection, 8197 of whom were given treatment consisting of two experimental vaccines targeting [[Subtypes of HIV|HIV types B and E]] that are prevalent in Thailand, while 8198 were given a placebo. The participants were tested for HIV every six months for three years. After three years, the vaccine group saw HIV infection rates reduced by more than 30% compared with those in the placebo group. However, after taking into account the seven people who had HIV infections at the time of their vaccination (two in the placebo group, five in the vaccine group) the percentage dropped to 26%.<ref name=Harmon2009/><ref name=Rerks-Ngarm2009>{{cite journal
|author=Rerks-Ngarm S
|title=Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand
|journal=[[The New England Journal of Medicine|NEJM]]
|volume=361 |issue=23 |pages=2209&ndash;2220
|year=2009 |month=November
|pmid=19843557 |doi=10.1056/NEJMoa0908492 |url=http://www.nejm.org/doi/full/10.1056/NEJMoa0908492
|archiveurl=<!--http://www.webcitation.org/5mEyyRZ06--> |archivedate=<!--23 December 2009-->
|author-separator=,
|author2=Pitisuttithum P |author3=Nitayaphan S |display-authors=3 |last4=Kaewkungwal |first4=Jaranit
|last5=Chiu |first5=Joseph |last6=Paris |first6=Robert |last7=Premsri |first7=Nakorn |last8=Namwat
|first8=Chawetsan |last9=De Souza |first9=Mark
}}</ref>
 
Further analysis presented at a 2011 AIDS conference in Bangkok revealed that participants receiving vaccines in the RV 144 trial who produced [[IgG]] antibodies against the V2 loop of the [[Envelope glycoprotein GP120|HIV outer envelope]] were 43% less likely to become infected than those who did not, while [[IgA]] production was associated with a 54% greater risk of infection than those who did not produce the antibodies (but not worse than placebo).  Viruses collected from vaccinated participants possessed mutations in the V2 region.  Tests of a vaccine for [[SIV]] in monkeys found greater resistance to SIV in animals producing antibodies against this region.  For these reasons further vaccine development was expected to focus heavily on vaccines designed to provoke an IgG reaction against the V2 loop.<ref>{{cite web
|url=http://www.nature.com/news/2011/110916/full/news.2011.541.html
|title=Clues emerge to explain first successful HIV vaccine trial |author=Ewen Callaway |date=16 September 2011
}}</ref>
 
===Planned clinical trials===
Novel approaches, including [[modified vaccinia Ankara]] (MVA), [[adeno-associated virus]], [[Venezuelan Equine Encephalitis]] (VEE) replicons, and codon-optimized DNA have proven to be strong inducers of CTL in macaque models, and have provided at least partial protection in some models. Most of these approaches are in, or will soon enter, clinical studies.
 
==Economics of vaccine development==
A June 2005 study estimates that $682 million is spent on AIDS vaccine research annually ([http://www.iavi.org/viewfile.cfm?fid=30892 CITE]).
 
Economic issues with developing an AIDS vaccine include the need for advance purchase commitment (or  [[advance market commitments]]) because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to [[marginal cost]] ([http://papers.ssrn.com/sol3/papers.cfm?abstract_id=696741 CITE]).
 
Conducting trials of HIV vaccines in the countries most affected by the epidemic is a challenge,[76] albeit one that has been successfully met in Thailand. When one or more HIV-1 vaccines are identified, the task will be just beginning. The next step will be ensuring access for populations where the need is the greatest. Currently, over 60 million people have become infected with HIV-1 and hundreds of millions are at risk. Many of these individuals have little access to medical care, no access to adult vaccinations and live in countries where the per capita expenditure on health care is a few dollars.  
 
HIV-1 is poorly understood and often stigmatized. Diagnostic tests or algorithms may need to be altered. Education will be needed to convey not only the value but the anticipated limitations of the vaccines, so that other preventive strategies will be maintained. The role of community organizations in maintaining this balance will be critical ([http://www.avac.org www.avac.org]).
Regulatory approvals in numerous countries will be required. The issues in the USA are complex.[77] Internationally, there are greater challenges. If a vaccine has not been demonstrated to be universally effective against every HIV-1 subtype, the standard paradigm of approval in one or more industrialized countries followed years or even decades later by acceptance in and distribution to developing countries will not apply. Both the governments of countries affected by HIV-1 and the international regulatory and health authorities must plan ahead for the advent of an HIV-1 vaccine to avoid unnecessary delays.
 
HIV-1 vaccines might induce [[antibody]] responses that would completely prevent HIV-1 infection by strains of virus that are sufficiently well matched to the vaccine. Unfortunately, HIV-1 evolves continuously both within an individual (the source of infection) and within human populations. Therefore, a vaccinated person might be protected initially, but later encounter a virus against which he or she is not immune. Multivalent vaccines or repeated immunization with an updated vaccine may be required for continued protection. Thus, eventually, one might imagine licensure not of a specific HIV-1 vaccine but of a method for producing the vaccine and its updated versions, somewhat analogous to the annual updates of influenza vaccine.
 
The scientific challenges involved in discovery of a safe and effective vaccine against HIV-1, although daunting, are only the prelude. The task of developing and deploying a vaccine against HIV-1 will be enormous (i.e. gaining licensure and scaling up to produce vaccine for worldwide distribution, developing distribution methods and establishing purchase mechanisms will require an unprecedented co-operative effort by governments, international agencies, philanthropic organizations and the private sector).[78] Recent recognition of the importance of controlling HIV-1 for public health, economic and political stability has been encouraging and there has been substantial growth in academic, government, nonprofit and pharmaceutical industry vaccine research, but the fight is not over. Stopping the march of the pandemic will conserve economic and human resources needed to care for those already infected. Ending the HIV-1 epidemic is critical to allow economic development and promote political stability in the developing world and to reduce loss of life and suffering worldwide.
 
==Controversy==
Some conservatives, such as [[Reginald Finger|Reginald Finger, M.D., M.P.H.]], a member of the Advisory Committee on Immunization Practices (ACIP) in the U.S., have stated that the Committee would have to carefully consider an HIV vaccine's effects on sexual activity. ACIP is a government committee linked to the Centers for Disease Control. ACIP is charged with advising the President on prevention of vaccine-related diseases. Dr. Finger's term expired in June, 2006.
 
Similar controversy has arisen in response to the recent introduction of the [[HPV vaccine]], which prevents infection with certain strains of [[human papillomavirus]], another sexually transmitted disease.
 
==Transgenic plants==
[[Transgenic plants]] can be a convenient and efficient way to obtain HIV vaccine.
*Plant-based vaccines, which are easy to produce and administer, and require no cold chain for their heat stability are, in principle, suited to such a strategy.
*More recently, it has been shown that even highly immunogenic, enveloped plant-based vaccines can be produced at a competitive and more efficient rate than conventional strategies.
*The high variability of HIV epitopes and the need to stimulate both humoral neutralizing antibodies and cellular immunity suggest the importance of using the plant system: it offers a wide range of possible strategies, from single-epitope to multicomponent vaccines, modulators of the immune response (adjuvants) and preventive molecules (microbicides), either alone or in association with plant-derived monoclonal antibodies, besides the potential use of the latter as therapeutic agents.  
*Furthermore, plant-based anti-HIV strategies can be administered not only parenterally but also by the more convenient and safer oral route, which is a more suitable approach for possible mass vaccination <ref>http://www.ncbi.nlm.nih.gov/pubmed?term=%20%20%20%2020673014</ref>.
*Plant-based HIV vaccines have already shown to be immonugenic <ref>http://www.ncbi.nlm.nih.gov/pubmed/15877601</ref>
 
==See also==
* [[Subunit HIV vaccine]]


==References==
==References==
{{reflist|2}}
{{Reflist|2}}
* Berman, P. W., Gregory, T. J., Riddle, L., Nakamura, G. R., Champe, M. A., Porter, J. P., Wurm, F. M., Hershberg, R. D., Cobb, E. K. and Eichberg, J. W. (1990) Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160. ''Nature'' '''345''', 622-625
* Connor, R. I., Korber, B. T., Graham, B. S., Hahn, B. H., Ho, D. D., Walker, B. D., Neumann, A. U., Vermund, S. H., Mestecky, J., Jackson, S., Fenamore, E., Cao, Y., Gao, F., Kalams, S., Kunstman, K. J., McDonald, D., McWilliams, N., Trkola, A., Moore, J. P. and Wolinsky, S. M. (1998) Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines. ''J. Virol.'' '''72''', 1552-1576
* McCutchan, F. E. (2000b) Understanding the genetic diversity of HIV-1. ''AIDS'' '''14''', S31-S44
* Peeters, M. and Sharp, P. M. (2000) Genetic diversity of HIV-1: the moving target. ''AIDS'' '''14''', S129-S140
* Poignard, P., Sabbe, R., Picchio, G. R., Wang, M., Gulizia, R. J., Katinger, H., Parren, P. W., Mosier, D. E. and Burton, D. R. (1999) Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. ''Immunity'' '''10''', 431-438
* Romano, L., Venturi, G., Giomi, S., Pippi, L., Valensin, P. E. and Zazzi, M. (2002) Development and significance of resistance to protease inhibitors in HIV-1 infected adults under triple-drug therapy in clinical practice. ''J. Med. Virol.' '''66''', 143-150
* Specter, Michael.  Political Science: The Bush Administration's war on the laboratory. The New Yorker. [[March 13]] [[2006]].
* UNAIDS (2004) Report on the global AIDS epidemic, July 2004
 
==External links==
 
* [http://www.vrc.nih.gov Vaccine Research Center (VRC)]- Information concerning Preventive HIV vaccine research studies
* [http://www.niaid.nih.gov/daids/vaccine/default.htm NIAID HIV vaccine site] ([[Division of Acquired Immunodeficiency Syndrome|DAIDS]])
* [http://www.vaccinealliance.org Global Alliance for Vaccines and Immunization (GAVI)]
* [http://www.iavi.org International AIDS Vaccine Initiative (IAVI)]
* [http://www.avac.org AIDS Vaccine Advocacy Coalition (AVAC)]
* [http://www.aidsvaccine.org Capital Area Vaccine Effort (CAVE]
* [http://briandeer.com/vaxgen-aidsvax.htm Investigation of first candidate vaccine]
* [http://blogs.cgdev.org/vaccine Vaccines for Development]
* [http://www.bethegeneration.org Be the Generation - Information on HIV Vaccine Clinical Research in 20 American Cities]
* [http://www.holdsworthhouse.com.au/clinical_about_research.php Australian recruiter for HIV treatment studies]
* [http://ec.europa.eu/research/health/poverty-diseases/projects/84_en.htm Aids Vaccine Integrated Project]  ''([[European Union]] research programme)''
*[http://www.aids.gov AIDS.gov - The U.S. Federal Domestic HIV/AIDS Resource]
*[http://www.HIVtest.org HIVtest.org - Find an HIV testing site near you]
 
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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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