Oral Coadministration of an Intramuscular DNA/Modified Vaccinia Ankara Vaccine for Simian Immunodeficiency Virus Is Associated with Better Control of Infection in Orally Exposed Infant Macaques

Abstract

The majority of human immunodeficiency virus (HIV) type 1 infections in infants are acquired orally through breastfeeding. Toward development of a pediatric HIV vaccine to prevent breastmilk transmission, we tested the efficacy of a simultaneous oral and intramuscular (IM) vaccination regimen for preventing oral simian immunodeficiency virus (SIV) transmission in infant rhesus macaques. Two groups of neonatal macaques were immunized with DNA encoding SIV virus-like particles (DNA-SIV) on weeks 0 and 3, then boosted with modified vaccinia Ankara (MVA) virus expressing SIV antigens (MVA-SIV) on weeks 6 and 9. One group was prime/boosted by the IM route only. Another group was immunized with DNA by both the IM and topical oral (O) buccal routes, and boosted with MVA-SIV by both the IM and sublingual (SL) routes. A third group of control animals received saline by O + IM routes on weeks 0 and 3, and empty MVA by SL + IM routes on weeks 6 and 9. On week 12, infants were orally challenged once weekly with SIV mac251 until infected. The vaccine regimen that included oral routes resulted in reduced peak viremia. The rate of infection acquisition in vaccinated infants was found to be associated with prechallenge intestinal immunoglobulin G (IgG) responses to SIV gp120 and V1V2. Peak viremia was inversely correlated with postinfection intestinal IgG responses to gp120, gp41, and V1V2. These results suggest that codelivery of a pediatric HIV vaccine by an oral route may be superior to IM-only regimens for generating mucosal antibodies and preventing HIV breastmilk transmission in neonates.

Oral clade C SHIV challenge models to study pediatric HIV-1 infection by breastmilk transmission

“…This regimen resulted in systemic SIV infection in >80% of infants within 2 weeks after the first exposure, but had the drawback that, as inoculations were all provided in a narrow time window, it was not possible to identify which inoculation induced infection (21, 28). We subsequently developed a repeated weekly oral SIV mac251 exposure model (33–35). The virological outcome of this repeated weekly challenge strategy was highly consistent; in studies spanning 3 years, the estimated risk of infection per exposure ranged from 0.23-0.25 (33–35).…”

“…We subsequently developed a repeated weekly oral SIV mac251 exposure model (33–35). The virological outcome of this repeated weekly challenge strategy was highly consistent; in studies spanning 3 years, the estimated risk of infection per exposure ranged from 0.23-0.25 (33–35). Animals exhibited high peak viremia (median: 4.8×10 7 copies/ ml) and viremia persisted at high levels (at week 8 post-infection [PI]: median: 1.1×10 7 copies/ ml) (Figure 1).…”

“…Each curve represents a single infant macaque orally infected with SIV mac251 by a repeated weekly exposure regimen (n=21). The data represent a summary of three independent studies in three subsequent years, indicated by different shades as specified in the graph legend (33–35). Plasma viremia is graphed in relation to the number of viral exposures.…”

“…The pediatric SIV mac251 infection model has been extensively utilized to study early host responses (20–24), test new treatment strategies (25–27), and to optimize pediatric HIV vaccine strategies (28–32). To further increase the translational value of the pediatric oral SIV mac251 infection model, the single high-dose challenge has been replaced by a repeated weekly oral SIV mac251 exposure model to more closely resemble actual HIV exposures in human infants (33–35).…”

Analytical treatment interruption after short-term anti-retroviral therapy in a postnatally SHIV infected infant rhesus macaque model

“…Formalin fixed, paraffin embedded tissue sections were seqentially cut (5 µm) and stained for CD3 and CD20 (Table S2) as previously described (58, 59). SHIV RNA was visualized with the 1-Plex ViewRNA TM ISH Tissue Assay Kit using SIV mac239 or Beta actin (positive control) probe sets and ViewRNA Chromogenic Signal Amplification Kit (ThermoFisher, Waltham, MA).…”