Immunogenicity of viral vector, prime-boost SIV vaccine regimens in infant rhesus macaques: Attenuated vesicular stomatitis virus (VSV) and modified vaccinia Ankara (MVA) recombinant SIV vaccines compared to live-attenuated SIV

Abstract

In a previously developed infant macaque model mimicking HIV infection by breast feeding, we demonstrated that intramuscular immunization with recombinant poxvirus vaccines expressing simian immunodeficiency virus (SIV) structural proteins provided partial protection against infection following oral inoculation with virulent SIV. In an attempt to further increase systemic but also local antiviral immune responses at the site of viral entry, we tested the immunogenicity of different orally administered, replicating vaccines. One group of newborn macaques received an oral prime immunization with a recombinant vesicular stomatitis virus expressing SIVmac239 gag, pol and env (VSV-SIVgpe), followed 2 weeks later by an intramuscular boost immunization with MVA-SIV. Another group received two immunizations with live-attenuated SIVmac1A11, administered each time both orally and intravenously. Control animals received mock immunizations or non-SIV VSV and MVA control vectors. Analysis of SIV-specific immune responses in blood and lymphoid tissues at 4 weeks of age demonstrated that both vaccine regimens induced systemic antibody responses and both systemic and local cell-mediated immune responses. The safety and immunogenicity of the VSV-SIVgpe +MVA-SIV immunization regimen described in this report provide the scientific incentive to explore the efficacy of this vaccine regimen against virulent SIV exposure in the infant macaque model.

Accelerated Heterologous Adenovirus Prime-Boost SIV Vaccine in Neonatal Rhesus Monkeys

“…Both ALVAC and MVA vectors expressing SIV antigens administered to infant rhesus monkeys afforded partial protection against repeated low-dose exposures of SIVmac251, but detailed immunologic characteristics of the vaccine-elicited immune responses were not reported (38). Similarly, vesicular stomatitis virus (VSV) vectors have been tested alone and in combination with MVA vectors in this model (23,37). Our data with rAd vectors similarly show that viral vaccine vectors are immunogenic in neonates.…”

“…A neonatal HIV-1 vaccine that rapidly induces systemic and mucosal protective immunity would therefore represent a major advance. A variety of HIV-1 vaccine candidates have been studied with adults, but very few studies of HIV-1 vaccines have been performed in neonates (2,8,23,25,26,37,38,40). Considering the unique features of the neonatal immune system and the need to induce mucosal immune responses rapidly to protect newborns from breast milk HIV-1 transmission, it is important to investigate the immunogenicity of candidate HIV-1 vaccines directly in neonates.…”

“…First, neonates have immature immune systems, and it is unclear whether vaccine vectors that are immunogenic in adults will be comparably immunogenic in neonates. Very few studies of HIV-1 or simian immunodeficiency virus (SIV) vaccines have been performed with neonatal rhesus monkeys (23,37,38,40) and humans (8,25,26). Moreover, heterologous prime-boost regimens that have been studied with adult rhesus monkeys (5,7,22) typically require 6 months or longer to induce peak immune responses, and such timing would not be optimal for a pediatric HIV-1 vaccine.…”

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

“…As found for most pediatric SIV vaccines (5)(6)(7)(8), vaccination of infant macaques with the M. tuberculosis-SIV prime/MVA-SIV boost regimen was not able to prevent oral SIV acquisition in infant macaques. However, a subset of vaccinated infants was able to partially control viremia throughout the study period.…”

Evidence for an Increased Risk of Transmission of Simian Immunodeficiency Virus and Malaria in a Rhesus Macaque Coinfection Model

“…T cell activation and proliferation of CD4-positive T cells (CD3 clone SP34-2 and CD4 clone L200) were defined by using antibodies to CCR5 (clone 3A9) and to Ki67 (clone B56), respectively. Samples were acquired on a FACS ARIA apparatus (Beckton-Dickinson), and data were analyzed using FlowJo software (TreeStar; Ashland, OR) as described previously (30,48). Data are reported as the frequency of CD3 ϩ CD4 ϩ lymphocytes that stained positive for an individual marker.…”