Adjuvant-Dependent Enhancement of HIV Env-Specific Antibody Responses in Infant Rhesus Macaques

Abstract

Toward the goal of developing an effective HIV vaccine that can be administered in infancy to protect against postnatal and lifelong sexual HIV transmission risks, the current pilot study was designed to compare the effect of novel adjuvants on the induction of HIV Env-specific antibody responses in infant macaques. Aligning our studies with the adjuvanted proteins evaluated in a prime-boost schedule with ALVAC in the ongoing HVTN (HIV Vaccine Trials Network) 702 efficacy trial, we selected the bivalent clade C Env immunogens gp120 C.1086 and gp120 TV1 in combination with the MF59 adjuvant. However, we hypothesized that the adjuvant system AS01, that is included in the pediatric RTS,S malaria vaccine, would promote Env-specific antibody responses superior to those of the oil-in-water MF59 emulsion adjuvant. In a second study arm, we compared two emulsions, glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) and 3M-052-SE, containing Toll-like receptor 4 (TLR4) and TLR7/TLR8 (TLR7/8) ligand, respectively. The latter adjuvant had been previously demonstrated to be especially effective in activating neonatal antigen-presenting cells. Our results demonstrate that different adjuvants drive quantitatively or qualitatively distinct responses to the bivalent Env vaccine. AS01 induced higher Env-specific plasma IgG antibody levels than the antigen in MF59 and promoted improved antibody function in infants, and 3M-052-SE outperformed GLA-SE by inducing the highest breadth and functionality of antibody responses. Thus, distinct adjuvants are likely to be required for maximizing vaccine-elicited immune responses in infants, particularly when immunization in infancy aims to elicit both perinatal and lifelong immunity against challenging pathogens such as HIV. Alum remains the adjuvant of choice for pediatric vaccines. Yet the distinct nature of the developing immune system in infants likely requires novel adjuvants targeted specifically at the pediatric population to reach maximal vaccine efficacy with an acceptable safety profile. The current study supports the idea that additional adjuvants for pediatric vaccines should be, and need to be, tested in infants for their potential to enhance immune responses. Using an infant macaque model, our results suggest that both AS01 and 3M-052-SE can significantly improve and better sustain HIV Env-specific antibody responses than alum. Despite the limited number of animals, the results revealed interesting differences that warrant further testing of promising novel adjuvant candidates in larger preclinical and clinical studies to define the mechanisms leading to adjuvant-improved antibody responses and to identify targets for adjuvant and vaccine optimization.

HIV Env-Specific IgG Antibodies Induced by Vaccination of Neonatal Rhesus Macaques Persist and Can Be Augmented by a Late Booster Immunization in Infancy

“…In addition, we were able to further substantiate our earlier finding that the Toll-like receptor 7/8 (TLR7/8)-based adjuvant 3M-052 in stable emulsion (SE) is superior in inducing Env-specific antibody responses compared to a squalene-based adjuvant that was tested in a previous study ( Fig. 1) (13).…”

“…These data and findings from our earlier pediatric HIV Env vaccine strategies in the nonhuman primate model (12)(13)(14) provided the premise for our study described here. In those studies, aimed at developing a pediatric HIV vaccine to prevent breastmilk transmission of HIV, we documented that infant rhesus macaques can develop durable HIV Env-specific antibody responses (12).…”

“…In those studies, aimed at developing a pediatric HIV vaccine to prevent breastmilk transmission of HIV, we documented that infant rhesus macaques can develop durable HIV Env-specific antibody responses (12). Env-specific antibody responses were enhanced by extending the intervals between immunizations and by applying adjuvants that act as agonists to Toll-like receptors instead of the commonly used aluminum hydroxide (alum) in pediatric vaccines (12,13). Consistent with the data from early human pediatric vaccine trials (10), we also observed persistence of Env-specific antibody responses after vaccination in early life (12).…”

“…Impact of adjuvant on vaccine-induced antibody responses. In our efforts to optimize pediatric HIV vaccine strategies, we had previously compared different vac- cine strategies, vaccine intervals, and various adjuvants with the goal to enhance Env-specific antibody responses (12,13). As part of these studies, we had applied a similar MVA/Env regimen (12), but in the prior study, the 1086.C protein was given by the intranasal route (200 g) adjuvanted with the TLR7/8 agonist R848 (25 g) and by the intramuscular (i.m.)…”

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

“…The oral SIV mac251 infection model in infant rhesus macaques simulates the most important aspects of HIV acquisition by breastfeeding in human infants (19). 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).…”