Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys

Barouch, Dan H.; O’Brien, Kara L.; Simmons, Nathaniel L.; King, Sharon L.; Abbink, Peter; Maxfield, Lori F.; Sun, Ying-Hua Betty; Porte, Annalena La; Riggs, Ambryice M.; Lynch, Diana M.; Clark, Sarah L.; Backus, Katherine; Perry, James; Seaman, Michael S.; Carville, Angela; Mansfield, Keith G.; Szinger, James; Fischer, Will; Muldoon, Mark; Korber, Bette T.

doi:10.1038/nm.2089

Cited by 349 publications

(321 citation statements)

References 20 publications

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“…Immunogens designed in this way to include only the multidimensionally constrained regions of the HIV proteome, which also contain epitopes presented by diverse HLAs in a population, are candidates for peptide vaccines using synthetic vectors (26), or by linking each segment together, they can be analogs of mosaic immunogens (27) delivered by traditional vectors. Such an immunogen would target the most vulnerable regions of HIV rather than the whole proteome.…”

Section: Discussionmentioning

confidence: 99%

Coordinate linkage of HIV evolution reveals regions of immunological vulnerability

Dahirel

Shekhar

Pereyra

et al. 2011

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

189

263

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Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated (“HIV sectors”). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses.

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Section: Discussionmentioning

confidence: 99%

Coordinate linkage of HIV evolution reveals regions of immunological vulnerability

Dahirel

Shekhar

Pereyra

et al. 2011

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

189

263

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“…In vivo experiments are, however, required to validate the approach for HCV. Experimental studies of mosaics in HIV-1 can be considered as proof of principle: mosaics can be synthesized and expressed and are immunogenic in animal models, and the total number and cross-reactivity of CD8 + and CD4 + T-cell responses are increased relative to natural and consensus antigens (Barouch et al, 2010;Kong et al, 2009;Santra et al, 2010). The T-cell mosaic antigen insert design could be used together with improvements in other areas of vaccine design.…”

Section: Discussionmentioning

confidence: 99%

“…Mosaic sets elicited multiple CD4 + and CD8 + responses, and the breadth of responses was many-fold higher than the responses to natural-strain antigens (Kong et al, 2009) when assayed using peptides that contain the most common epitope variants found in the sampled global diversity (Li et al, 2006). Similarly promising results were obtained in recently completed studies in macaques: HIV-1 mosaic antigens elicited responses with greater breadth (more responses to diverse variants overall) and greater depth (more variants recognized per response) than did natural strains (Barouch et al, 2010;Santra et al, 2010).…”

Section: Introductionmentioning

confidence: 93%

Genotype 1 and global hepatitis C T-cell vaccines designed to optimize coverage of genetic diversity

Yusim

Fischer

Yoon

et al. 2010

Journal of General Virology

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Immunological control of hepatitis C virus (HCV) is possible and is probably mediated by host T-cell responses, but the genetic diversity of the virus poses a major challenge to vaccine development. We considered monovalent and polyvalent candidates for an HCV vaccine, including natural, consensus and synthetic 'mosaic' sequence cocktails. Mosaic vaccine reagents were designed using a computational approach first applied to and demonstrated experimentally for human immunodeficiency virus type 1 (HIV-D). Mosaic proteins resemble natural proteins, but are assembled from fragments of natural sequences via a genetic algorithm and optimized to maximize the coverage of potential T-cell epitopes (all 9-mers) found in natural sequences and to minimize the inclusion of rare 9-mers to avoid vaccine-specific responses. Genotype 1-specific and global vaccine cocktails were evaluated. Among vaccine candidates considered, polyvalent mosaic sequences provided the best coverage of both known and potential epitopes and had the fewest rare epitopes. A global vaccine based on conserved proteins across genotypes may be feasible, as a five-antigen mosaic cocktail provided 90, 77 and 70 % coverage of the Core, NS3 and NS4 proteins, respectively; protein coverage diminished with increased protein variability, dropping to 38 % for NS2. For the genotype 1-specific vaccine, the H77 prototype vaccine sequence matched only 50 % of the potential epitopes in the population, whilst a polyprotein three-antigen mosaic cocktail increased potential epitope coverage to 83 %. More than 75 % coverage of all HCV proteins was achieved with a three-antigen mosaic cocktail, suggesting that genotype-specific vaccines could also include the more variable proteins. INTRODUCTIONAn estimated 170 million people are infected with hepatitis C virus (HCV) worldwide (Armstrong et al., 2000;Lauer & Walker, 2001). Acute HCV infection leads to chronic infection in 70-80 % of infected individuals (Alter et al., 1999;Conry-Cantilena et al., 1996) and can result in liver cirrhosis, liver failure and hepatocellular carcinoma (Lauer & Walker, 2001). The current treatment with pegylated alpha interferon and the nucleoside analogue ribavirin has improved clinical outcomes (Davis et al., 1998;Fried et al., 2002; Manns et al., 2001;Zeuzem et al., 2000), but is expensive and requires sophisticated medical management, which is out of reach for the majority of infected people. Development of a prophylactic vaccine to prevent the spread of HCV infection remains paramount.Several findings indicate that immunological control of HCV is possible. In humans and chimpanzees, spontaneous eradication of HCV can occur during acute infection (Cooper et al., 1999; Gerlach et al., 1999Gerlach et al., , 2003Lechner et al., 2000; Thimme et al., 2001). Spontaneously cleared HCV infection reduced the likelihood of developing a chronic infection in continuously exposed drug users (Mehta et al., 2002). Reinfection after initial clearance had a shorter duration and a lower peak viraemia in the ch...

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“…38 In particular, mosaic HIV Env vaccines delivered in adenovirus or by modified vaccinia Ankara (MVA), a replication-deficient viral vector, demonstrated a strong protective effect against infection by a subsequent simian human immunodeficiency virus challenge. 39 Currently, a phase-I clinical trial is recruiting participants to assess the safety and tolerability of MVA-HIV Env mosaic vaccine in healthy adult participants.…”

Section: Dealing With Hiv-1 Genetic Diversitymentioning

confidence: 99%

Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production

Oyarzún

Kobe

2015

Human Vaccines & Immunotherapeutics

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Novel vaccination approaches based on rational design of B-and T-cell epitopes -epitope-based vaccinesare making progress in the clinical trial pipeline. The epitope-focused recombinant protein-based malaria vaccine (termed RTS,S) is a next-generation approach that successfully reached phase-III trials, and will potentially become the first commercial vaccine against a human parasitic disease. Progress made on methods such as recombinant DNA technology, advanced cell-culture techniques, immunoinformatics and rational design of immunogens are driving the development of these novel concepts. Synthetic recombinant proteins comprising both B-and T-cell epitopes can be efficiently produced through modern biotechnology and bioprocessing methods, and can enable the induction of large repertoires of immune specificities. In particular, the inclusion of appropriate CD4+ T-cell epitopes is increasingly considered a key vaccine component to elicit robust immune responses, as suggested by results coming from HIV-1 clinical trials. In silico strategies for vaccine design are under active development to address genetic variation in pathogens and several broadly protective "universal" influenza and HIV-1 vaccines are currently at different stages of clinical trials. Other methods focus on improving population coverage in target populations by rationally considering specificity and prevalence of the HLA proteins, though a proof-of-concept in humans has not been demonstrated yet. Overall, we expect immunoinformatics and bioprocessing methods to become a central part of the next-generation epitope-based vaccine development and production process.

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Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys

Cited by 349 publications

References 20 publications

Coordinate linkage of HIV evolution reveals regions of immunological vulnerability

Coordinate linkage of HIV evolution reveals regions of immunological vulnerability

Genotype 1 and global hepatitis C T-cell vaccines designed to optimize coverage of genetic diversity

Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production

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