Safety and Immunogenicity of Novel Recombinant BCG and Modified Vaccinia Virus Ankara Vaccines in Neonate Rhesus Macaques

Abstract

Although major inroads into making antiretroviral therapy available in resource-poor countries have been made, there is an urgent need for an effective vaccine administered shortly after birth, which would protect infants from acquiring human immunodeficiency virus type 1 (HIV-1) through breast-feeding. Bacillus Calmette-Guérin (BCG) is given to most infants at birth, and its recombinant form could be used to prime HIV-1-specific responses for a later boost by heterologous vectors delivering the same HIV-1-derived immunogen. Here, two groups of neonate Indian rhesus macaques were immunized with either novel candidate vaccine BCG.HIVA 401 or its parental strain AERAS-401, followed by two doses of recombinant modified vaccinia virus Ankara MVA.HIVA. The HIVA immunogen is derived from African clade A HIV-1. All vaccines were safe, giving local reactions consistent with the expected response at the injection site. No systemic adverse events or gross abnormality was seen at necropsy. Both AERAS-401 and BCG.HIVA 401 induced high frequencies of BCG-specific IFN-␥-secreting lymphocytes that declined over 23 weeks, but the latter failed to induce detectable HIV-1-specific IFN-␥ responses. MVA.HIVA elicited HIV-1-specific IFN-␥ responses in all eight animals, but, except for one animal, these responses were weak. The HIV-1-specific responses induced in infants were lower compared to historic data generated by the two HIVA vaccines in adult animals but similar to other recombinant poxviruses tested in this model. This is the first time these vaccines were tested in newborn monkeys. These results inform further infant vaccine development and provide comparative data for two human infant vaccine trials of MVA.HIVA.

Priming with a Recombinant Pantothenate Auxotroph of Mycobacterium bovis BCG and Boosting with MVA Elicits HIV-1 Gag Specific CD8+ T Cells

“…Safety issues are also of concern with the use of BCG as a HIV vaccine vector and this has led to auxotroph BCG strains being considered as alternative vectors for immuocompromised individuals [28]. These mutant strains do not show compromised immunogenicity in animal studies [20], [24], [36]. The ΔpanCD BCG auxotroph has previously been shown to require pantothenate supplementation to grow in human macrophages and is nonpathogenic in SCID mice.…”

Impact of Poxvirus Vector Priming, Protein Coadministration, and Vaccine Intervals on HIV gp120 Vaccine-Elicited Antibody Magnitude and Function in Infant Macaques

“…Acknowledging the caveat of relatively small group sizes, few studies have compared different vaccine regimens side-by-side in infants (43). Overall, the extended-interval regimen induced superior functional responses, such as broader ADCC activity and stronger intestinal IgA responses.…”

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

“…In fact, among the new TB vaccine candidates under development, several are based on additional attenuations of M. bovis within the existing BCG vaccine or on attenuated M. tuberculosis strains similar to the auxotroph AMtb vaccines used here (17)(18)(19)(20)(21). Recombinant BCG strains expressing HIV antigens are also in development as potential HIV vaccines and have been tested in mice (22)(23)(24) and in adult (25)(26)(27)(28)(29) and neonatal (30) macaques. Considering the high risk of HIV and TB infection in infants, especially in sub-Saharan Africa, we deemed it important to understand how novel TB vaccines or combination HIV-TB vaccines might impact HIV acquisition.…”