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Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection.

ABSTRACT: An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8(+) T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8(+) T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1(+) patients significantly correlated with high CD4(+) T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development.

SUBMITTER: Ondondo B

PROVIDER: S-EPMC4886941 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection.

Ondondo Beatrice B Murakoshi Hayato H Clutton Genevieve G Abdul-Jawad Sultan S Wee Edmund G-T EG Gatanaga Hiroyuki H Oka Shinichi S McMichael Andrew J AJ Takiguchi Masafumi M Korber Bette B Hanke Tomáš T

Molecular therapy : the journal of the American Society of Gene Therapy 20160108 4

An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effectiv ...[more]

PMID: 26743582

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Project description:UnlabelledNeutralizing antibodies (NAbs) targeting glycoprotein E2 are important for the control of hepatitis C virus (HCV) infection. One conserved antigenic site (amino acids 412 to 423) is disordered in the reported E2 structure, but a synthetic peptide mimicking this site forms a β-hairpin in complex with three independent NAbs. Our structure of the same peptide in complex with NAb 3/11 demonstrates a strikingly different extended conformation. We also show that residues 412 to 423 are essential for virus entry but not for E2 folding. Together with the neutralizing capacity of the 3/11 Fab fragment, this indicates an unexpected structural flexibility within this epitope. NAbs 3/11 and AP33 (recognizing the extended and β-hairpin conformations, respectively) display similar neutralizing activities despite converse binding kinetics. Our results suggest that HCV utilizes conformational flexibility as an immune evasion strategy, contributing to the limited immunogenicity of this epitope in patients, similar to the conformational flexibility described for other enveloped and nonenveloped viruses.ImportanceApproximately 180 million people worldwide are infected with hepatitis C virus (HCV), and neutralizing antibodies play an important role in controlling the replication of this major human pathogen. We show here that one of the most conserved antigenic sites within the major glycoprotein E2 (amino acids 412 to 423), which is disordered in the recently reported crystal structure of an E2 core fragment, can adopt different conformations in the context of the infectious virus particle. Recombinant Fab fragments recognizing different conformations of this antigenic site have similar neutralization activities in spite of converse kinetic binding parameters. Of note, an antibody response targeting this antigenic region is less frequent than those targeting other more immunogenic regions in E2. Our results suggest that the observed conformational flexibility in this conserved antigenic region contributes to the evasion of the humoral host immune response, facilitating chronicity and the viral spread of HCV within an infected individual.

Project description:BackgroundCOVID-19 vaccine coverage and experiences of structural and attitudinal barriers to vaccination vary across populations. Education-related inequality in COVID-19 vaccine coverage and barriers within and between countries can provide insight into the hypothesised role of education as a correlate of vaccine access and acceptability. We aimed to characterise patterns of within-country education-related inequality in COVID-19 vaccine indicators across 90 countries.MethodsThis study used data from the University of Maryland Social Data Science Center Global COVID-19 Trends and Impact Survey. Data from 90 countries (more than 14 million participants aged 18 years and older) were included in our analyses. We assessed education-related inequalities globally, across country-income groupings, and nationally for four indicators (self-reported receipt of COVID-19 vaccine, structural barriers to vaccination, vaccine hesitancy, and vaccine refusal) for the study period June 1-Dec 31, 2021. We calculated an absolute summary measure of inequality to assess the latest situation of inequality and time trends and explored the association between government vaccine availability policies and education-related inequality.FindingsNearly all countries had higher self-reported receipt of a COVID-19 vaccine among the most educated respondents than the least educated respondents. Education-related inequality in structural barriers, vaccine hesitancy, and vaccine refusal varied across countries, and was most pronounced in high-income countries, overall. Low-income and lower-middle-income countries reported widespread experiences of structural barriers and high levels of vaccine hesitancy alongside low levels of education-related inequality. Globally, vaccine hesitancy in unvaccinated people was higher among those with lower education and vaccine refusal was higher among those with higher education, especially in high-income countries. Over the study period, education-related inequalities in self-reported receipt of a COVID-19 vaccine declined, globally and across all country income groupings. Government policies expanding vaccine availability were associated with lower education-related inequality in self-reported receipt of vaccine.InterpretationThis study serves as a baseline for continued inequality monitoring and could help to inform targeted actions for the equitable uptake of vaccines.FundingGavi, the Vaccine Alliance.

Dataset Information

Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection.

Publications

Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection.

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