Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques

Shingai, Masashi; Donau, Olivia K.; Plishka, Ronald J.; Buckler-White, Alicia; Mascola, John R.; Nabel, Gary J.; Nason, Martha; Montefiori, David C.; Moldt, Brian; Poignard, Pascal; Diskin, Ron; Björkman, Pamela J.; Eckhaus, Michael; Klein, Florian; Mouquet, Hugo; Lorenzi, Julio C. C.; Gazumyan, Anna; Burton, Dennis R.; Nussenzweig, Michel C.; Martin, Malcolm A.; Nishimura, Yoshiaki

doi:10.1084/jem.20132494

Cited by 290 publications

(272 citation statements)

References 59 publications

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“…Multiple vaccine studies in NHPs and humans have implied that functional antibody responses against Env are necessary for protective immunity (3,18,32). Furthermore, passive administration of nmAbs to RMs has unambiguously been shown to provide protection against mucosal SHIV infection (5-13), with in vitro serum nAb IC 50 titers in the range of ∼1:200 emerging as predictive of protection (7,12,14). However, it was not known whether these low to moderate nAb titers would extend to vaccine-elicited antibody protection, as previous studies have reported a disconnect between in vitro nAb and a protective effect (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, passive administration of neutralizing monoclonal antibodies (nmAbs) to nonhuman primates (NHPs) has repeatedly been shown to provide robust protection against mucosal infection with a chimeric human/simian immunodeficiency virus, even at modest in vitro nAb IC 50 titers that are readily achievable by vaccination (5)(6)(7)(8)(9)(10)(11)(12)(13)(14). NHP studies have also demonstrated that protection against heterologous SIV challenge is feasible and likely mediated by antibody responses (15)(16)(17)(18).…”

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confidence: 99%

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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%

mentioning

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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“…Some of these bNAbs exhibit remarkable breadth and potency in vitro, and many of these bNAbs can prevent infection in animal models when passively administered at low doses before challenge (11)(12)(13)(14). Therefore, it is widely believed that a vaccine that could elicit such antibodies would be protective against infection, and the development of such a vaccine remains an important goal.…”

Section: Introductionmentioning

confidence: 99%

Towards HIV-1 remission: potential roles for broadly neutralizing antibodies

Halper-Stromberg¹,

Nussenzweig²

2016

Journal of Clinical Investigation

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“…Studies involving the passive transfer of bnAbs in nonhuman primates have been promising. Suppression of viremia in infected monkeys and prevention of viral acquisition in uninfected monkeys was observed in these studies [54][55][56]. Moreover marked suppression of HIV production in viral reservoirs by bnAbs has also been detected in ex vivo studies [57].…”

Section: Current Status Of Hiv Vaccine Research Landscapementioning

confidence: 66%

HIV Vaccine Development: Current Scenario and Future Prospects

Ajbani¹

2016

J AIDS Clin Res

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The search for a preventive vaccine that can halt the global pandemic is the ultimate goal of HIV research. Development of a vaccine against HIV-1 has been plagued by many insurmountable challenges. Different vaccine concepts have been tested to overcome these challenges. Experimental vaccines that showed promise in preclinical studies were advanced into clinical trials. Yet, human trials proved to be a huge disappointment until the results of the RV144 trial in Thailand. This trial not only provided the first evidence of a modest efficacy, but also valuable insights on the possible immunologic correlates of vaccine protection. Currently, the HIV vaccine research landscape has been rejuvenated by two major developments. On one hand, there has been a resurgence of interest in T cell-based vaccines with the promising results obtained using a recombinant cytomegalovirus vector vaccine. On the other hand, the discovery of more than a hundred broadly neutralizing antibodies from cohorts of HIV-infected individuals has led to the development of antibody-based preventive vaccines. Innovations in the design of vaccines, vaccination strategies and clinical trial programs will be necessary to accelerate the search for a prophylactic HIV vaccine. This article reviews the current status of HIV vaccine research and provides a roadmap to future efforts in vaccine development.

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Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques

Cited by 290 publications

References 59 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

Towards HIV-1 remission: potential roles for broadly neutralizing antibodies

HIV Vaccine Development: Current Scenario and Future Prospects

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