Optimizing HIV‐1‐specific CD8⁺ T‐cell induction by recombinant BCG in prime‐boost regimens with heterologous viral vectors

Abstract

The desire to induce HIV-1-specific responses soon after birth to prevent breast milk transmission of HIV-1 led us to propose a vaccine regimen which primes HIV-1-specific T cells using a recombinant Mycobacterium bovis bacillus Calmette-Gué rin (rBCG) vaccine. Because attenuated live bacterial vaccines are typically not sufficiently immunogenic as stand-alone vaccines, rBCG-primed T cells will likely require boost immunization(s). Here, we compared modified Danish (AERAS-401) and Pasteur lysine auxotroph (222) strains of BCG expressing the immunogen HIVA for their potency to prime HIV-1-specific responses in adult BALB/c mice and examined four heterologous boosting HIVA vaccines for their immunogenic synergy. We found that both BCG.HIVA 401 and BCG.HIVA 222 primed HIV-1-specific CD8 1 T-cell-mediated responses. The strongest boosts were delivered by human adenovirus-vectored HAdV5.HIVA and sheep atadenovirus-vectored OAdV7.HIVA vaccines, followed by poxvirus MVA.HIVA; the weakest was plasmid pTH.HIVA DNA. The prime-boost regimens induced T cells capable of efficient in vivo killing of sensitized target cells. We also observed that the BCG.HIVA 401 and BCG.HIVA 222 vaccines have broadly similar immunologic properties, but display a number of differences mainly detected through distinct profiles of soluble intercellular signaling molecules produced by immune splenocytes in response to both HIV-1-and BCG-specific stimuli. These results encourage further development of the rBCG prime-boost regimen.Key words: BCG . HIV . Mother-to-child transmission . Prime-boost . T cells . Vaccines Supporting Information available online IntroductionIt is 30 years since the first cases of AIDS were described, yet HIV-1 infection continues to take its toll particularly in resourcepoor areas such as many parts of sub-Saharan Africa [1]. About half of the infected adults are women of childbearing age, who will expose their babies to HIV-1 during pregnancy, delivery and breastfeeding [2]. Although antiretroviral treatment substantially decreases mother-to-child transmission (MTCT) of HIV-1 [3], it is not ideal due to the cost, requirement for daily compliance, side effects and possible development of drug resistance. Because breast milk provides essential nutrients and protection against 3542other diseases in the early days of life [4,5], formula as an HIV-1-free alternative is recommended only if it is acceptable, feasible, affordable, sustainable and safe (AFASS) and thus it is not an option for many HIV-1-positive mothers in Africa. The best hope for protecting newborns and infants in the 'South' (and in the 'North') against acquiring HIV-1 from their infected mothers while breastfeeding remains the development of safe, effective and accessible adult and pediatric vaccines [6]. For babies born to HIV-1-positive mothers, induction of anti-HIV-1 immunity as soon as possible after birth is highly desirable and may provide a basis for lifetime protection, which can be maintained by boosts later in life.A successful HIV-1 vaccine may ...

The influence of delivery vectors on HIV vaccine efficacy

“…The potential use of BCG as an HIV vaccine vector was explored in preclinical studies of adult and new-born BALB/c mice using the HIV-1 clade A Gag immunogen (HIVA) (Mwau et al, 2004). Priming with recombinant BCG expressing HIVA (BCG.HIVA) induced HIV-specific T cell responses which were efficiently boosted with rMVA (MVA.HIVA) (Hopkins et al, 2011a,b; Saubi et al, 2011, 2012). In further related studies, priming with BCG.HIVA and boosting with a combination vaccine expressing HIVA and the Mtb antigen 85A (mMVA.HIVA.85A) induced robust IFN-γ-producing T cells to both HIV-1 and Mtb antigens.…”

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

“…Therefore, it has been proposed that novel TB vaccine candidates should aim to preserve these unique features of BCG. 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.…”

Robust Immunity to an Auxotrophic Mycobacterium bovis BCG-VLP Prime-Boost HIV Vaccine Candidate in a Nonhuman Primate Model

“…rBCG vaccines have been shown to efficiently prime the immune response to the heterologous antigen in recombinant adenovirus, recombinant poxvirus, and protein prime-boost combinations (24,26,27,30,57,58). We (27,44,52) and others (59) have previously shown that a Gag VLP boost, used in heterologous prime-boost modality, is a (62).…”

“…Mycobacterium bovis BCG has been investigated as a live vaccine vector for a variety of human infections (20)(21)(22)(23)(24)(25), including HIV-1 infections (26)(27)(28)(29)(30). An important and attractive feature of using BCG is its long safety record as a tuberculosis (TB) vaccine, having being injected into over 3 billion people worldwide.…”