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. 2016 Feb 11;3(1):ofw034.
doi: 10.1093/ofid/ofw034. eCollection 2016 Jan.

Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine

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Free PMC article

Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine

Venkateswarlu Chamcha et al. Open Forum Infect Dis. .
Free PMC article

Abstract

Background. In this study, we analyzed the protective efficacy of a simian immunodeficiency virus (SIV) macaque 239 (SIVmac239) analogue of the clinically tested GOVX-B11 deoxyribonucleic acid (DNA)/modified vaccinia Ankara (MVA) human immunodeficiency virus vaccine. Methods. The tested vaccine used a DNA immunogen mutated to mimic the human vaccine and a regimen with DNA deliveries at weeks 0 and 8 and MVA deliveries at weeks 16 and 32. Twelve weekly rectal challenges with 0.3 animal infectious doses of SIV sootey mangabey E660 (SIVsmE660) were administered starting at 6 months after the last immunization. Results. Over the first 6 rectal exposures to SIVsmE660, <10-year-old tripartite motif-containing protein 5 (TRIM5)α-permissive rhesus macaques showed an 80% reduction in per-exposure risk of infection as opposed to a 46% reduction in animals over 10 years old; and, over the 12 challenges, they showed a 72% as opposed to a 10% reduction. Analyses of elicited immune responses suggested that higher antibody responses in the younger animals had played a role in protection. Conclusions. The simian analogue of the GOVX-B11 HIV provided strong protection against repeated rectal challenges in young adult macaques.

Keywords: DNA/MVA vaccine; HIV vaccine; SIV; age-dependent protection; antibody.

Figures

Figure 1.
Figure 1.
Schematic of trial: Kaplan–Meier curves for vaccine-elicited prevention of infection and vaccine efficacy. (A) Schematic showing the vaccination and challenge schedule for the trial. (B) Kaplan-Meier curves for prevention of infection in all vaccinated and control animals separated by age. Granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvanted and nonadjuvanted vaccine groups were pooled for analysis. (C) Kaplan-Meier curves for prevention of infection in tripartite motif-containing protein 5 (TRIM5)α-permissive animals separated by age. (D) Vaccine efficacy. (E) Number of transmitted variants. For details, see Methods. Abbreviations: CI, confidence interval; Cont, controls; All Vac, combined groups; shaded area, first 6 challenges.
Figure 2.
Figure 2.
Simian immunodeficiency virus (SIV) macaque 239 (SIVmac239)-specific antibody (Ab) responses and their correlations with protection. (A) Levels of elicited glycoprotein (gp)140-specific immunoglobulin (Ig)G in serum. (B) Specific activity of elicited gp140-specific IgG in rectal secretions. (C) The gp140-specific IgG Ab-secreting cells (ASCs); (D) gp140-specific IgA ASCs. Antibody responses in serum and rectal secretions were measured at peak response (2 weeks after the final modified vaccinia Ankara [MVA] boost) and prechallenge (week 52). Antibody-secreting cells were measured at day 5 after the second (final) MVA boost. For each panel, the left figure shows the magnitudes of responses elicited by the GM-CSF coexpressing and non-coexpressing vaccines, and the right panel shows the correlation between the elicited Ab or ASC and the number of challenges to infection. Data are for all animals. For Ab to gp140 in serum, rectal secretions, and Ab-dependent cellular cytotoxicity, correlations are for prechallenge responses (week 52). For ASC, correlations are for 5 days after the second MVA boost. Abbreviations: DDMM, DNA at 0 and 2 months and MVA at 4 and 8 months; DgDgMM, same regimen for DNA coexpressing GMCSF. MVA2, second MVA inoculation; PBMC, peripheral blood mononuclear cells; peak, week 34; Pre, before first immunization; Pre-chall, week 52; shaded area, background.
Figure 3.
Figure 3.
Antibody (Ab) responses that did not show significant correlations with protection. (A) Avidity index measured against simian immunodeficiency virus (SIV) macaque 239 (SIVmac239) glycoprotein (gp)160. (B) Serum Ab-dependent cellular phagocytosis (ADCP) score measured against SIVsmE660gp140. (C) Serum Ab-dependent cellular cytotoxicity (ADCC) values measured at peak against SIVmac239 infected cells. (D) Serum neutralizations titers measured in TZM-bl cells against the indicated viruses at peak (2 weeks after the last modified vaccinia Ankara [MVA] boost) and prechallenge time points (52 weeks). Abbreviations: Cont, controls; DDMM, DNA at 0 and 8 weeks, MVA at 16 and 32 weeks; DgDgMM, same regimen for GM-CSF co-expressing DNA. ID50, inhibitory dose for 50% neutralization.
Figure 4.
Figure 4.
Effect of age on antibody (Ab) responses. Levels of elicited immunoglobulin (Ig)G are shown on the left and correlations with number of challenges to infection are on the right. (A) Levels of elicited glycoprotein (gp)140-specific IgG in serum. (B) Specific activity of elicited gp140-specific IgG in rectal secretions. (C) Magnitudes of neutralizing Ab against the challenge virus. (D) Antibody-dependent cellular cytotoxicity (ADCC) titer. Responses were measured at peak response (2 weeks after the final modified vaccinia Ankara boost) and prechallenge (week 52). For each panel, the left panels show the magnitudes of responses elicited for all animals in the 2 age groups, and the right panels show the correlation between the elicited Ab at peak and prechallenge timepoints and the number of challenges to infection. In the right panels, the color of points indicates whether data were from a GM-CSF-adjuvanted or nonadjuvanted animal. Abbreviations: AUC, area under the curve; ID50, inhibitory dose for 50% neutralization; Peak, week 34; Pre, preimmunization; pre-chall, week 52; shaded areas, background of detection; SIVmac239, simian immunodeficiency virus macaque 239.
Figure 5.
Figure 5.
Temporal postinfection viremia. (A) Temporal viremia for all animals based on vaccination in the presence or absence of coexpressed granulocyte-macrophage colony-stimulating factor in the deoxyribonucleic acid prime. (B) Temporal viremia for pooled vaccine groups that were <10 years old. (C) Temporal viremia for pooled vaccine groups that were more than 10 years old. In each panel, the left figure presents data for all animals, the middle figure presents data for tripartite motif-containing protein 5 (TRIM5)α-permissive animals, and the right figure presents data for TRIM5α-restrictive animals. Points with significant differences are indicted by asterisks: *P ≤ .05; **P ≤ .01. Abbreviations: All Vac, combined groups; DDMM, DNA at 0 and 8 weeks and MVA at 16 and 32 weeks; DgDgMM, the same regimen for the GM-CSF co-expressing DNA; RNA, ribonucleic acid.

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References

    1. Smith JM, Amara RR, McClure HM et al. Multiprotein HIV-1 clade B DNA/MVA vaccine: construction, safety, andimmunogenicity in Macaques. AIDS Res Hum Retroviruses 2004; 20:654–65. - PubMed
    1. Wyatt LS, Belyakov IM, Earl PL et al. Enhanced cell surface expression, immunogenicity and genetic stability resulting from a spontaneous truncation of HIV Env expressed by a recombinant MVA. Virology 2008; 372:260–72. - PMC - PubMed
    1. Goepfert PA, Elizaga ML, Sato A et al. Phase 1 safety and immunogenicity testing of DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. J Infect Dis 2011; 203:610–9. - PMC - PubMed
    1. Goepfert PA, Elizaga ML, Seaton K et al. Specificity and 6-month durability of immune responses induced by DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. J Infect Dis 2014; 210:99–110. - PMC - PubMed
    1. Lai L, Kwa S, Kozlowski PA et al. Prevention of infection by a granulocyte-macrophage colony-stimulating factor co-expressing DNA/modified vaccinia Ankara simian immunodeficiency virus vaccine. J Infect Dis 2011; 204:164–73. - PMC - PubMed
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