Lessons from the RV144 Thai Phase III HIV-1 Vaccine Trial and the Search for Correlates of Protection

Kim, Jerome H.; Excler, Jean–Louis; Michael, Nelson L.

doi:10.1146/annurev-med-052912-123749

Cited by 159 publications

(144 citation statements)

References 93 publications

(118 reference statements)

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“…Identifying the immune correlates of protection against HIV/SIV continues to be a central pursuit for the vaccine research community (29)(30)(31). Multiple vaccine studies in NHPs and humans have implied that functional antibody responses against Env are necessary for protective immunity (3,18,32).…”

Section: Discussionmentioning

confidence: 99%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Although the correlates of immunological protection from human immunodeficiency virus or simian immunodeficiency virus infection remain incompletely understood, it is generally believed that medium to high titers of serum neutralizing antibodies (nAbs) against the challenge virus will prevent infection. This paradigm is based on a series of studies in which passive transfer of HIV-specific nAbs protected rhesus macaques (RMs) from subsequent mucosal challenge with a chimeric human/simian immunodeficiency virus. However, it is unknown whether nAb titers define protection in the setting of active immunization. Here we determined serum nAb titers against breakthrough transmitted/founder (T/F) SIVsmE660-derived envelope glycoprotein (Env) variants from 14 RMs immunized with SIVmac239-based DNA-prime/modified vaccinia virus Ankara-boost vaccine regimens that included GM-CSF or CD40L adjuvants and conferred significant but incomplete protection against repeated low-dose intrarectal challenge. A single Env variant established infection in all RMs except one, with no identifiable genetic signature associated with vaccination breakthrough compared with T/F Envs from four unvaccinated monkeys. Breakthrough T/F Env pseudoviruses were potently neutralized in vitro by heterologous pooled serum from chronically SIVsmE660-infected monkeys at IC50 titers exceeding 1:1,000,000. Remarkably, the T/F Env pseudoviruses from 13 of 14 monkeys were also susceptible to neutralization by autologous prechallenge serum at in vitro IC50 titers ranging from 1:742–1:10,832. These titers were similar to those observed in vaccinated RMs that remained uninfected. These data suggest that the relationship between serum nAb titers and protection from mucosal SIV challenge in the setting of active immunization is more complex than previously recognized, warranting further studies into the balance between immune activation, target cell availability, and protective antibody responses.

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Section: Discussionmentioning

confidence: 99%

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Burton

Kilgore

Smith

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Attenuated form of vaccine shows the strongest method to induce the protection in many NHP [109]. But in human testing, this research is ruled out due to safety [106,107].…”

Section: Developmental Study Of Hiv Vaccinementioning

confidence: 98%

“…The pre-specified immune correlates analysis showed that antibodies which are used against the gp120's region of V1V2 possesses an important role to protect from acquirement of HIV-1 and that envelope of plasma which is Env-specific IgA form of antibodies correlates directly with the risk [109].…”

Section: Developmental Study Of Hiv Vaccinementioning

confidence: 99%

Efficacy Trials and Progress of HIV Vaccines

Asif¹,

Irshad²

2017

J Cell Sci Ther

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Discovery of HIV as causative agent of AIDS let to the belief that a vaccine for AIDS will be available shortly but was not that easy, and it took more than 30 years of hard laboratory and clinical work toward HIV vaccine development. Efficacy trials of RV144 and their results revealed that HIV vaccine is accomplishable. Clinical trials for developing bNAbs has monoclonal antibodies and to increase its half-life are also underway to achieve a proper HIV vaccine. In this review article, we see that how these efficacy trials are highlighting HIV vaccine concepts in clinical development. Therapeutic vaccines are proving to be a functional cure toward HIV treatment and progress is ongoing in such HIV vaccine development which will attack HIV before it fuses with cell and cause infection thus preventing AIDS. So, in near future it will be possible to cure HIV and bring an end to this epidemic.

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“…48 Subsequently a number of studies further exploring the potential mechanisms of protection of RV144 have been performed. [50][51][52] Sieve analysis comparing sequences of breakthrough virus isolates found that isolates from vaccine recipients were less likely to have a lysine at K169 of the Env V2 region than placebo recipients, suggesting selective effects of vaccine induced immune responses on V1V2 on breakthrough HIV-1 viruses. 53 Further characterization of RV144 vaccine-induced V2 Ab found that the Ab recognized both conformational (on gp70-V1V2) and linear epitopes (residues 165-178, immediately N-terminal to the putative a4b7 binding motif in the mid-loop region of V2) and were cross-reactive with the V1V2 regions from many HIV-1 subtypes (A, B, C and CRF01_AE).…”

Section: Rv144mentioning

confidence: 99%

Progress in HIV-1 vaccine development

2014

Journal of Allergy and Clinical Immunology

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Lessons from the RV144 Thai Phase III HIV-1 Vaccine Trial and the Search for Correlates of Protection

Cited by 159 publications

References 93 publications

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

Efficacy Trials and Progress of HIV Vaccines

Progress in HIV-1 vaccine development

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