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Immune Correlate-Guided HIV Vaccine Design

2018; Cell Press; Volume: 24; Issue: 1 Linguagem: Inglês

10.1016/j.chom.2018.06.012

ISSN

1934-6069

Autores

Galit Alter, Dan H. Barouch,

Tópico(s)

Immune Cell Function and Interaction

Resumo

Although vaccines have been successfully developed against several pathogens, designing an effective vaccine to protect against human immunodeficiency virus (HIV) has remained an intractable challenge. To address this, the research community has looked to human and non-human primate studies to understand the correlates of protective immunity, based on which a targeted vaccine strategy may be designed. Two distinct approaches, focused on different immune correlates of protection, have emerged. The first focuses on structure-based design of HIV envelope immunogens that are able to induce antibodies that neutralize the virus. The second focuses on strategies aimed at driving non-neutralizing polyclonal and polyfunctional antibodies that engage other arms of immunity to clear the virus. Here we review these two different vaccine design strategies and posit that ultimately the convergence of these two efforts will likely be necessary for the development of a globally protective HIV vaccine. Although vaccines have been successfully developed against several pathogens, designing an effective vaccine to protect against human immunodeficiency virus (HIV) has remained an intractable challenge. To address this, the research community has looked to human and non-human primate studies to understand the correlates of protective immunity, based on which a targeted vaccine strategy may be designed. Two distinct approaches, focused on different immune correlates of protection, have emerged. The first focuses on structure-based design of HIV envelope immunogens that are able to induce antibodies that neutralize the virus. The second focuses on strategies aimed at driving non-neutralizing polyclonal and polyfunctional antibodies that engage other arms of immunity to clear the virus. Here we review these two different vaccine design strategies and posit that ultimately the convergence of these two efforts will likely be necessary for the development of a globally protective HIV vaccine. Despite the growing understanding of human immunodeficiency virus (HIV) disease pathogenesis and the structure of its key antigenic targets, efforts to develop effective vaccines against HIV (Rappuoli and Aderem, 2011Rappuoli R. Aderem A. A 2020 vision for vaccines against HIV, tuberculosis and malaria.Nature. 2011; 473: 463-469Crossref PubMed Scopus (179) Google Scholar) continue to fail (Ouattara and Laurens, 2015Ouattara A. Laurens M.B. Vaccines against malaria.Clin. Infect. Dis. 2015; 60: 930-936Crossref PubMed Scopus (43) Google Scholar). This reflects our lack of understanding of the key immunologic responses required for protection. While antibodies serve as the primary correlate of protection following most clinically approved vaccines (Delany et al., 2013Delany I. Rappuoli R. Seib K.L. Vaccines, reverse vaccinology, and bacterial pathogenesis.Cold Spring Harb. Perspect. Med. 2013; 3: a012476Crossref PubMed Google Scholar, Dormitzer et al., 2008Dormitzer P.R. Ulmer J.B. Rappuoli R. Structure-based antigen design: a strategy for next generation vaccines.Trends Biotechnol. 2008; 26: 659-667Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar), antibody levels alone do not always represent the mechanistic correlate of immunity (Plotkin, 2008Plotkin S.A. Vaccines: correlates of vaccine-induced immunity.Clin. Infect. Dis. 2008; 47: 401-409Crossref PubMed Scopus (495) Google Scholar). Even the most sophisticated protein design approaches continue to confer only limited protection against HIV (Sanders et al., 2015Sanders R.W. van Gils M.J. Derking R. Sok D. Ketas T.J. Burger J.A. Ozorowski G. Cupo A. Simonich C. Goo L. et al.HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers.Science. 2015; 349: aac4223Crossref PubMed Scopus (308) Google Scholar), suggesting that qualitatively superior, rather than higher-magnitude, antibodies are required to provide protection from infection. Thus, it is likely that vaccine design platforms centered around the identification and induction of immunologically relevant mechanisms of HIV control, linked to antigen design strategies, may be critical for the development of effective HIV vaccines. This review examines the principles of designing a vaccine aimed at selectively augmenting immunological correlates of protection, including viral neutralization, with a specific focus on the ongoing strategies for HIV vaccine design. In the nearly four decades since the discovery of HIV as the etiologic agent of acquired immunodeficiency syndrome (AIDS), four major vaccine concepts have been tested for clinical efficacy (Corey et al., 2015Corey L. Gilbert P.B. Tomaras G.D. Haynes B.F. Pantaleo G. Fauci A.S. Immune correlates of vaccine protection against HIV-1 acquisition.Sci. Transl. Med. 2015; 7: 310rv7Crossref PubMed Scopus (113) Google Scholar, Stephenson and Barouch, 2013Stephenson K.E. Barouch D.H. A global approach to HIV-1 vaccine development.Immunol. Rev. 2013; 254: 295-304Crossref PubMed Scopus (48) Google Scholar, Stephenson et al., 2016Stephenson K.E. D'Couto H.T. Barouch D.H. New concepts in HIV-1 vaccine development.Curr. Opin. 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Conversely, one vaccine strategy showed a modest level of protection in humans, resulting in 31% protection (Rerks-Ngarm et al., 2009Rerks-Ngarm S. Pitisuttithum P. Nitayaphan S. Kaewkungwal J. Chiu J. Paris R. Premsri N. Namwat C. de Souza M. Adams E. et al.MOPH-TAVEG InvestigatorsVaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.N. Engl. J. Med. 2009; 361: 2209-2220Crossref PubMed Scopus (2195) Google Scholar). However, despite this modest signal, this vaccine approach challenged classic dogma, as protection was observed in the absence of neutralizing antibodies and cytotoxic T cell responses. Intense immunological dissection of vaccine-induced protective and non-protective responses uncovered higher levels of non-neutralizing IgG antibodies targeting the second variable loop (V2) in the HIV envelope protein, higher levels of HIV envelope gp120-specific antibodies able to engage natural killer (NK) cells and drive antibody-dependent cellular cytotoxicity (ADCC), and lower levels of HIV envelope-specific IgA responses in protected individuals (vaccinees) (Haynes et al., 2012aHaynes B.F. Gilbert P.B. McElrath M.J. Zolla-Pazner S. Tomaras G.D. Alam S.M. Evans D.T. Montefiori D.C. Karnasuta C. Sutthent R. et al.Immune-correlates analysis of an HIV-1 vaccine efficacy trial.N. Engl. J. Med. 2012; 366: 1275-1286Crossref PubMed Scopus (1249) Google Scholar). 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Pietzsch J. Seaman M.S. Nussenzweig M.C. Ravetch J.V. Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity.Cell. 2014; 158: 1243-1253Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, Hessell et al., 2007Hessell A.J. Hangartner L. Hunter M. Havenith C.E. Beurskens F.J. Bakker J.M. Lanigan C.M. Landucci G. Forthal D.N. Parren P.W. et al.Fc receptor but not complement binding is important in antibody protection against HIV.Nature. 2007; 449: 101-104Crossref PubMed Scopus (629) Google Scholar). Thus two major parallel tracks for HIV vaccine development are being explored (Figure 1). One approach involves the design of vaccines to induce neutralizing antibodies (Burton et al., 2012Burton D.R. Ahmed R. Barouch D.H. Butera S.T. Crotty S. Godzik A. Kaufmann D.E. McElrath M.J. Nussenzweig M.C. Pulendran B. et al.A blueprint for HIV vaccine discovery.Cell Host Microbe. 2012; 12: 396-407Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar), while a second approach focuses on the design of vaccines to drive functional antiviral non-neutralizing antibodies (Gray et al., 2016Gray G.E. Laher F. Lazarus E. Ensoli B. Corey L. Approaches to preventative and therapeutic HIV vaccines.Curr. Opin. Virol. 2016; 17: 104-109Crossref PubMed Google Scholar, Stephenson and Barouch, 2013Stephenson K.E. Barouch D.H. A global approach to HIV-1 vaccine development.Immunol. Rev. 2013; 254: 295-304Crossref PubMed Scopus (48) Google Scholar, Stephenson et al., 2016Stephenson K.E. D'Couto H.T. Barouch D.H. New concepts in HIV-1 vaccine development.Curr. Opin. Immunol. 2016; 41: 39-46Crossref PubMed Scopus (53) Google Scholar). Here we propose that the integration of these two approaches is likely to have the highest probability of success. Over the past decade, the extraordinary pace of bNAb discovery has led to the identification of a limited number of sites of neutralization vulnerability on the HIV envelope (Burton and Hangartner, 2016Burton D.R. Hangartner L. Broadly neutralizing antibodies to HIV and their role in vaccine design.Annu. Rev. Immunol. 2016; 34: 635-659Crossref PubMed Google Scholar, Burton and Mascola, 2015Burton D.R. Mascola J.R. Antibody responses to envelope glycoproteins in HIV-1 infection.Nat. Immunol. 2015; 16: 571-576Crossref PubMed Scopus (264) Google Scholar, Kovacs et al., 2014Kovacs J.M. Noeldeke E. Ha H.J. Peng H. Rits-Volloch S. Harrison S.C. Chen B. Stable, uncleaved HIV-1 envelope glycoprotein gp140 forms a tightly folded trimer with a native-like structure.Proc. Natl. Acad. Sci. USA. 2014; 111: 18542-18547Crossref PubMed Scopus (42) Google Scholar). However, while sophisticated advances in our understanding of HIV envelope structure have revolutionized our capacity to make immunogens that limit exposure to distracting (Rutten et al., 2018Rutten L. Lai Y.T. Blokland S. Truan D. Bisschop I.J.M. Strokappe N.M. Koornneef A. van Manen D. Chuang G.Y. Farney S.K. et al.A universal Approach to optimize the folding and stability of prefusion-closed HIV-1 envelope trimers.Cell Rep. 2018; 23: 584-595Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, Sanders et al., 2015Sanders R.W. van Gils M.J. Derking R. Sok D. Ketas T.J. Burger J.A. Ozorowski G. Cupo A. Simonich C. Goo L. et al.HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers.Science. 2015; 349: aac4223Crossref PubMed Scopus (308) Google Scholar) non-neutralizing sites on the viral envelope, these antigens continue to fail to drive neutralizing antibodies with sufficient magnitude and breadth of neutralization in preclinical studies (Kovacs et al., 2014Kovacs J.M. Noeldeke E. Ha H.J. Peng H. Rits-Volloch S. Harrison S.C. Chen B. Stable, uncleaved HIV-1 envelope glycoprotein gp140 forms a tightly folded trimer with a native-like structure.Proc. Natl. Acad. Sci. USA. 2014; 111: 18542-18547Crossref PubMed Scopus (42) Google Scholar, Sanders et al., 2015Sanders R.W. van Gils M.J. Derking R. Sok D. Ketas T.J. Burger J.A. Ozorowski G. Cupo A. Simonich C. Goo L. et al.HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers.Science. 2015; 349: aac4223Crossref PubMed Scopus (308) Google Scholar). These monoclonal bNAbs have pointed to the need for extensive somatic hypermutation, mutations in framework regions, and the selection of rare long CDR3 loops (Burton et al., 2012Burton D.R. Ahmed R. Barouch D.H. Butera S.T. Crotty S. Godzik A. Kaufmann D.E. McElrath M.J. Nussenzweig M.C. Pulendran B. et al.A blueprint for HIV vaccine discovery.Cell Host Microbe. 2012; 12: 396-407Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, Burton and Mascola, 2015Burton D.R. Mascola J.R. Antibody responses to envelope glycoproteins in HIV-1 infection.Nat. Immunol. 2015; 16: 571-576Crossref PubMed Scopus (264) Google Scholar) as key to targeting sites of viral neutralization. These unusual characteristics, some that are naturally typically eliminated during normal B cell development (Haynes et al., 2005Haynes B.F. Fleming J. St Clair E.W. Katinger H. Stiegler G. Kunert R. Robinson J. Scearce R.M. Plonk K. 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