Alphavirus Replicon DNA Expressing HIV Antigens Is an Excellent Prime for Boosting with Recombinant Modified Vaccinia Ankara (MVA) or with HIV gp140 Protein Antigen

Abstract

Vaccination with DNA is an attractive strategy for induction of pathogen-specific T cells and antibodies. Studies in humans have shown that DNA vaccines are safe, but their immunogenicity needs further improvement. As a step towards this goal, we have previously demonstrated that immunogenicity is increased with the use of an alphavirus DNA-launched replicon (DREP) vector compared to conventional DNA vaccines. In this study, we investigated the effect of varying the dose and number of administrations of DREP when given as a prime prior to a heterologous boost with poxvirus vector (MVA) and/or HIV gp140 protein formulated in glucopyranosyl lipid A (GLA-AF) adjuvant. The DREP and MVA vaccine constructs encoded Env and a Gag-Pol-Nef fusion protein from HIV clade C. One to three administrations of 0.2 μg DREP induced lower HIV-specific T cell and IgG responses than the equivalent number of immunizations with 10 μg DREP. However, the two doses were equally efficient as a priming component in a heterologous prime-boost regimen. The magnitude of immune responses depended on the number of priming immunizations rather than the dose. A single low dose of DREP prior to a heterologous boost resulted in greatly increased immune responses compared to MVA or protein antigen alone, demonstrating that a mere 0.2 μg DREP was sufficient for priming immune responses. Following a DREP prime, T cell responses were expanded greatly by an MVA boost, and IgG responses were also expanded when boosted with protein antigen. When MVA and protein were administered simultaneously following multiple DREP primes, responses were slightly compromised compared to administering them sequentially. In conclusion, we have demonstrated efficient priming of HIV-specific T cell and IgG responses with a low dose of DREP, and shown that the priming effect depends on number of primes administered rather than dose.

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

“…This conclusion is further supported by the lack of anamnestic T cell responses and the absence of any upregulated cytokines normally associated with WT CHIKV infection. The successful results with the DREP platform show that a DNA launched replicon approach mimicking an infection by an RNA virus could be an alternative to conventional DNA vaccines, as significantly lower amounts of DNA (and number of doses) would be needed to achieve strong protective immune responses (4,14,45). A conventional DNA vaccine expressing the envelope antigens of CHIKV, a construct very similar to our D in terms of insert, has been previously evaluated in nonhuman primates (33).…”

Potent therapeutic efficacy of an alphavirus replicon DNA vaccine expressing human papilloma virus E6 and E7 antigens

“…These DNA replicon (DREP) vectors have been shown to elicit T cell responses superior to those of conventional plasmid DNA in preclinical studies against infectious agents such as human immunodeficiency virus or chikungunya virus. 18,19 This has also been demonstrated within the context of cancer vaccination. 20,21 Nevertheless, to date, no SFV-based DNA replicon vaccine has been explored as an alternative for VREP for eliciting effective anti-tumor immunity.…”

Replicon RNA Viral Vectors as Vaccines

“…Immunization with SFV particles expressing the Env [42] and gp41 [43] genes elicited humoral and cytotoxic T-lymphocyte (CTL) responses in mice. Interestingly, priming with a low dose (0.2 µg) DNA-based SFV replicon expressing the HIV Env and a Gag-Pol-Nef fusion prior to a heterologous boost with poxvirus (MVA) and/or HIV gp140 protein formulated in glycopyranosyl lipid A resulted in significantly enhanced immune responses [44]. Moreover, when macaques were immunized with a VSV vector carrying the SIV Env (smE660) gene neutralizing antibodies were obtained [46].…”