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. 2016 Jul 27;90(16):7285-7302.
doi: 10.1128/JVI.00481-16. Print 2016 Aug 15.

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

Kara Jensen  1 , Rafiq Nabi  2 , Koen K A Van Rompay  3 , Spencer Robichaux  2 , Jeffrey D Lifson  4 , Michael Piatak Jr  4 , William R Jacobs Jr  5 , Glenn Fennelly  5 , Don Canfield  3 , Katie R Mollan  6 , Michael G Hudgens  7 , Michelle H Larsen  5 , Angela M Amedee  2 , Pamela A Kozlowski  2 , Kristina De Paris  8
Affiliations

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

Kara Jensen et al. J Virol. .

Abstract

Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4(+) T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity.

Importance: Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses.

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Figures

FIG 1
FIG 1
Challenge outcome after repeated low-dose oral SIVmac251 exposure. (A and B) Plasma viremia in naive controls (A) and vaccinated animals (B). Starting at week 9 of age (black arrow), animals were exposed once weekly with 5,000 TCID50 of SIVmac251 by the oral route. Naive animals are shown as open circles, vaccinated animals with high and uncontrolled viremia (noncontrollers) are represented by black diamonds, and vaccinated animals that could partially control viremia (controllers) are shown as gray diamonds. The dashed line at 106 copies of SIV RNA/ml plasma indicates the threshold to define partial control of viremia in the current study, because most of the nonvaccinated animals had higher peak and chronic viremia throughout the study period. (C) Representing the per-exposure risk of SIV infection in naive control and vaccinated infant macaques, the Kaplan-Meier survival plot shows the percentage of naive and vaccinated animals that remain uninfected after each oral SIV exposure. (D) Median acute viremia (horizontal line), defined as area under the curve (AUC) of plasma viremia from weeks 1 to 3 post-SIV infection (PI) in controller and noncontroller animals of group B. (E) Analogous to panel D, but showing differences in early chronic viremia, defined as the AUC of plasma viremia between weeks 6 and 8 post-SIV infection in controller and noncontroller group B animals. Each symbol represents an individual animal.
FIG 2
FIG 2
SIV Env sequence diversity in naive and vaccinated animals. Phylogenetic tree depicting the 19 founder viral variants found in SIV-infected group A and B animals. The predominant gp160 variant found in the SIVmac251 inoculum (stock 6/04) was used to root the tree. The horizontal bar shows the scale of genetic distance. Sequence labels from group B vaccinated animals are boxed, and those from vaccinated controller animals are double boxed.
FIG 3
FIG 3
Prechallenge (week 9) SIV-specific T cell responses in group B vaccinated infant macaques. (A) SIV Gag-specific T cell responses in peripheral blood CD4+ (left) and CD8+ T cells (right). Each bar represents the sum of the percentage of single-cytokine-positive CD4+ or CD8+ T cells for a specific animal. Cytokine-positive T cells were measured by flow-cytometric analysis that included TNF-α (black), IL-17 (striped), IFN-γ (gray), and IL-2 (white). (B) Analogous data for SIV Env-specific T cell responses. N.T. (not tested) indicates that no cells were available for measuring SIV Env-specific responses in these animals. (C) Prechallenge (week 9) SIV Gag-specific CD4+ (left) and CD8+ T cell (right) responses were log transformed and plotted against acute peak viremia, defined as area under the curve of plasma viremia in weeks 1 to 3 post-SIV infection, to test for a potential correlation. Note that a value of 0.001 was assigned to animal number 42944, which did not have detectable T cell responses. (D) SIV Gag-specific CD4+ (left) and CD8+ (right) T cell responses at week 2 post-SIV infection were tested for their correlation with acute plasma viremia.
FIG 4
FIG 4
Vaccine-induced SIV Env-specific plasma IgG responses at week 9. (A) Plasma SIV gp140-specific IgG concentrations at weeks 0, 3, 6, and 9 in naive controls, noncontroller animals, and controller animals. The times of immunization and the vaccine constructs are indicated by arrows. (B) Plasma IgG concentrations for gp140, gp120, gp36, and gp70-V1V2 in controller and noncontroller animals at week 9, just prior to oral SIV challenge initiation. (C to E) Week 9 SIVmac251 neutralization titer (50%), ADP score, and avidity index for controller and noncontroller animals, respectively. (F) The correlation between anti-gp140 plasma IgG avidity at week 9 and acute viremia. (G) The gp140 plasma IgG avidity index for group B controller and noncontroller animals at the time of euthanasia. Nx, necropsy.
FIG 5
FIG 5
Vaccine-induced SIV Env-specific IgA responses prior to SIV challenge. (A) SIV gp140-specific plasma IgA levels at weeks 6 and 9 in naive animals, noncontroller animals, and controller animals. (B and C) gp140-specific IgA activity in saliva and fecal samples of controller and noncontroller animals at week 9. (D to F) Correlation between plasma, salivary, and fecal gp140-specific IgA at week 9 and acute viremia, respectively. (G) Linear positive correlation between salivary and fecal IgA at week 9. (H and I) Lack of correlation between plasma IgA and saliva IgA (H) or fecal IgA (I).
FIG 6
FIG 6
Postinfection salivary and fecal IgA antibodies in vaccinated animals. (A) Salivary SIV gp140-specific IgA activities at weeks 4 and 8 and at the time of euthanasia in controller and noncontroller animals. (B) Fecal gp140-specific IgA activities at weeks 2 and 6 and at the time of euthanasia in controller and noncontroller animals. The different time points in panels A and B are a result of sample availability. Nx, necropsy.
FIG 7
FIG 7
Postnatal antibody development in rhesus macaques. The analysis of plasma and salivary antibodies was performed using cross-sectional samples from infant macaques (black symbols) between the ages of 0 (birth) to 7 months (Mo). Adult antibody levels (open diamonds) are shown for comparison. The number of animals in each group is listed in parentheses below the relevant age group. Plasma and salivary total IgG levels (A and B) and plasma and salivary IgA levels (C and D) in infant compared to adult macaques are shown. Each symbol represents an individual animal, with horizontal bars indicating the median value. The nonparametric Mann-Whitney test was performed to determine differences between two specific infant age groups and between 6- to 7-month-old infants and adults. Note that a monomeric serum IgA standard was used to measure the polymeric IgA. Therefore, the total IgA is likely to be underestimated by a factor of 2.5.
FIG 8
FIG 8
Clinical assessment of SIV-infected animals. (A) The median disease score, determined by histological analysis, for animals in group A (naive controls) and group B animals at the time of euthanasia. Controller and noncontroller animals are represented by gray and black symbols, respectively. (B) The percentage of animals with detectable cryptosporidiosis in the colon and ileum of naive controls and vaccinated animals at the time of euthanasia. (C) SIV RNA (left y axis) and DNA levels (right y axis) were measured in colon tissue samples by PCR and are reported as copy numbers per 106 cell equivalents. (D) The percentage of CD4+ T cells within the CD3 population at the time of oral SIV challenge initiation (week 9), at weeks 1 to 2 (acute phase) and weeks 7 to 8 (chronic phase), and at the time of euthanasia in nonvaccinated animals and in controller and noncontroller vaccinated infant macaques. Median values per group are represented by horizontal bars. (E) Comparative analysis of CD4+ T cell frequencies in selected tissues of mock-vaccinated and vaccinated animals at the time of euthanasia. Differences between animals in 2 different groups were determined using the nonparametric Mann-Whitney test. Mes, mesenteric; Ret, retropharyngeal; Nx, necropsy.
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References

    1. WHO. 2014. Global update on the health sector response to HIV, 2014. World Health Organization, Geneva, Switzerland.
    1. Jensen K, Pena MG, Wilson RL, Ranganathan UD, Jacobs WR Jr, Fennelly G, Larsen M, Van Rompay KK, Kozlowski PA, Abel K. 2013. A neonatal oral-SIV prime/intramuscular MVA-SIV boost combination vaccine induces both SIV and -specific immune responses in infant macaques. Trials Vaccinol 2:53–63. doi:10.1016/j.trivac.2013.09.005. - DOI - PMC - PubMed
    1. Jensen K, Ranganathan UD, Van Rompay KK, Canfield DR, Khan I, Ravindran R, Luciw PA, Jacobs WR Jr, Fennelly G, Larsen MH, Abel K. 2012. A recombinant attenuated Mycobacterium tuberculosis vaccine strain is safe in immunosuppressed simian immunodeficiency virus-infected infant macaques. Clin Vaccine Immunol 19:1170–1181. doi:10.1128/CVI.00184-12. - DOI - PMC - PubMed
    1. Van Rompay KK, Abel K, Lawson JR, Singh RP, Schmidt KA, Evans T, Earl P, Harvey D, Franchini G, Tartaglia J, Montefiori D, Hattangadi S, Moss B, Marthas ML. 2005. Attenuated poxvirus-based simian immunodeficiency virus (SIV) vaccines given in infancy partially protect infant and juvenile macaques against repeated oral challenge with virulent SIV. J Acquir Immune Defic Syndr 38:124–134. doi:10.1097/00126334-200502010-00002. - DOI - PubMed
    1. Marthas ML, Van Rompay KK, Abbott Z, Earl P, Buonocore-Buzzelli L, Moss B, Rose NF, Rose JK, Kozlowski PA, Abel K. 2011. Partial efficacy of a VSV-SIV/MVA-SIV vaccine regimen against oral SIV challenge in infant macaques. Vaccine 29:3124–3137. doi:10.1016/j.vaccine.2011.02.051. - DOI - PMC - PubMed

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