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. 2011 Apr 12;29(17):3124-37.
doi: 10.1016/j.vaccine.2011.02.051. Epub 2011 Mar 4.

Partial efficacy of a VSV-SIV/MVA-SIV vaccine regimen against oral SIV challenge in infant macaques

Marta L Marthas  1 , Koen K A Van Rompay, Zachary Abbott, Patricia Earl, Linda Buonocore-Buzzelli, Bernard Moss, Nina F Rose, John K Rose, Pamela A Kozlowski, Kristina Abel
Affiliations

Partial efficacy of a VSV-SIV/MVA-SIV vaccine regimen against oral SIV challenge in infant macaques

Marta L Marthas et al. Vaccine. .

Abstract

Despite antiretroviral medications, the rate of pediatric HIV-1 infections through breast-milk transmission has been staggering in developing countries. Therefore, the development of a vaccine to protect vulnerable infant populations should be actively pursued. We previously demonstrated that oral immunization of newborn macaques with vesicular stomatitis virus expressing simian immunodeficiency virus genes (VSV-SIV) followed 2 weeks later by an intramuscular boost with modified vaccinia ankara virus expressing SIV (MVA-SIV) successfully induced SIV-specific T and B cell responses in multiple lymphoid tissues, including the tonsil and intestine [13]. In the current study, we tested the oral VSV-SIV prime/systemic MVA-SIV boost vaccine for efficacy against multiple oral SIVmac251 challenges starting two weeks after the booster vaccination. The vaccine did not prevent SIV infection. However, in vaccinated infants, the level of SIV-specific plasma IgA (but not IgG) at the time of challenge was inversely correlated with peak viremia. In addition, the levels of SIV-specific IgA in saliva and plasma were inversely correlated with viral load at euthanasia. Animals with tonsils that contained higher frequencies of SIV-specific TNF-α- or IFN-γ-producing CD8(+) T cells and central memory T cells at euthanasia also had lower viremia. Interestingly, a marked depletion of CD25(+)FoxP3(+)CD4(+) T cells was observed in the tonsils as well as the intestine of these animals, implying that T regulatory cells may be a major target of SIV infection in infant macaques. Overall, the data suggest that, in infant macaques orally infected with SIV, the co-induction of local antiviral cytotoxic T cells and T regulatory cells that promote the development of IgA responses may result in better control of viral replication. Thus, future vaccination efforts should be directed towards induction of IgA and mucosal T cell responses to prevent or reduce virus replication in infants.

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Figures

Figure 1
Figure 1
Plasma viremia and weight gain. Panels A and B show the longitudinal SIV viral levels in the plasma of unvaccinated and vaccinated macaques, respectively. Each symbol depicts an individual animal. The animals that were given a second round of challenges are shown in gray. Mamu A*01 positive animals are marked with an asteriks. Data are shown in relation to weeks post-infection (x-axis), and therefore all animals start at week 0. The black line marks the lower limit of SIV replication (10ˆ6) at viral set point measured in unvaccinated macaques. Panel C: Geometric means of SIV virus levels in unvaccinated (open symbol, dashed line) compared to vaccinated macaques (closed symbol, solid line) in the first 8 weeks after SIV infection. Panel D: The average weight gain for unvaccinated (dashed line) and vaccinated macaques (solid line) after SIV infection. The P value of <0.01 was obtained by regression analysis.
Figure 2
Figure 2
T cell activation and SIV-specific CD8+T cells in blood after SIV challenge. Panels A and B show the sum of the percentages of TNF-α producing CD8+T cells after in vitro stimulation with a SIV Gag p27 peptide pool and with AT-2 inactivated SIVmac239 in vaccinated and unvaccinated macaques, respectively, in the first 6 weeks after SIV challenge. The average frequencies of CCR5+ (Panel C) and Ki67+CD8+T cells (Panel D) in peripheral blood of vaccinated (closed symbol, solid line) and unvaccinated (open symbol, dashed line) macaques over time are presented.
Figure 3
Figure 3
Correlations between tonsil CD4+ and CD8+ memory T cell populations and plasma viral load at euthanasia. The percentages of central memory (TCM) (Panels A and C) and effector/ effector memory T cells (TEff ; Panels B and D) within the CD4+ (Panels A and B) or CD8+T cell population (Panels C and D) of the tonsils of vaccinated (closed symbols) and unvaccinated (open symbols) macaques are plotted against the SIV RNA copies per ml of plasma in the same animals at the time of euthanasia. Note that correlations were only statistically significant for vaccinated animals, and the P values and correlation coefficients are presented in each of the graphs. Due to limited cell numbers, data were only available for 5 of the 8 animals in each group (see text).
Figure 4
Figure 4
Cytokine-producing SIV-specific CD8+T cells in the tonsil of a vaccinated animal. Top panel: Frequencies of TNF-α producing CD8+T cells in medium and in SIVgag p27 stimulated cells. The SIV-specific TNF-α producing CD8+T cells were then further analyzed (bottom panels) to determine their differentiation status. The first plot shows the overall distribution of naïve (CD45RA+CCR7+), central memory (CD45RA-CCR7+) and effector/ effector memory (CD45RA+/- CCR7-) TNF-α producing CD8+T cells. The majority of TNF-α producing cells were found in the effector/ effector memory T cell population.
Figure 5
Figure 5
Longitudinal SIV-specific plasma IgG and IgA antibodies. Panel A: Shown are the concentrations of IgA (Panel A) and IgA (Panel B) antibodies against SIV Env (left) and SIV Gag, Pol (right) proteins measured by ELISA in plasma of each vaccinated and unvaccinated macaque before and after oral SIV challenge.
Figure 6
Figure 6
Correlation between SIV-specific antibodies and SIV replication levels. In Panel A and Panel B the correlation between peak plasma viremia and SIV Env-specific plasma IgA and IgG antibodies, respectively, at the time of challenge in vaccinated macaques is shown. Note that the two animals that did not develop SIV Env-specific IgA antibodies (#37902, #38130) were not included in Panel A, while Panel B includes all 8 vaccinees. Note that no correlation between plasma SIV-specific IgG antibody levels at the time of challenge and peak viremia was observed independent of whether all 8 vaccinees (see Panel B) or only the 6 vaccinated macaques (P=0.5472, r=-0.312) shown in Panel A were included in the analysis. In Panels C and D the specific activity (ng anti-SIV IgA antibody per μg total IgA) in plasma and saliva of each individual animal at the time of euthanasia is shown for vaccinated (C) and unvaccinated (D) animals. Animals with lowest to highest viremia are presented from left to right. Arrows denote salivary specimens that had specific activity than plasma from the same animal. Panels E and F demonstrate the inverse correlation between viral load and SIV Env (E) or SIV Gag, Pol (Panel F) IgA concentration in plasma or saliva of vaccinated animals at the time of euthanasia.
Figure 7
Figure 7
CD4+T cell frequencies and activation in peripheral blood. Panel A and Panel B show the average percentages of CD3+CD4+T cells within PBMC and the absolute numbers of CD3+CD4+T cells per microliter of blood, respectively, in peripheral blood of vaccinated and unvaccinated macaques. In Panels C and D, the change in the frequencies of CCR5+ (Panel C) or Ki67+ (Panel D) CD4+T cells after oral SIV infection are shown. Average values for vaccinated and unvaccinated macaques are presented with SEM.
Figure 8
Figure 8
Activation and loss of CD4+T cells in tissues. Panel A: Shown are average percentages of CD4+T cells within mononuclear cell populations from different tissues of age-matched (11 weeks) SIV-naïve (empty bars), unvaccinated (gray bars) and vaccinated macaques (dotted bars) at the time of euthanasia in comparison to the normal age-related decline of CD4+T cells in these tissues (week 4 to week 11 of age). Panel B shows the loss of activated CCR5 or Ki67-positive CD4+T cells, respectively, in tonsil and intestinal tissues of age-matched SIV-naïve (empty bars), in unvaccinated (gray bars) and in vaccinated macaques (dotted bars) at the time of euthanasia. In Panel C and Panel D the loss of CD25+CD4+T cells and CD25+FoxP3+CD4+T cells in tissues of unvaccinated and vaccinated macaques compared to SIV-naïve macaques is shown. Significant differences are indicated by the P values obtained after comparison of the SIV-naive and unvaccinated animals, the SIV-naive and vaccinated animals, and the unvaccinated and vaccinated animals.
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