Construction, Characterization, and Immunogenicity of a Multigene Modified Vaccinia Ankara (MVA) Vaccine Based on HIV Type 1 Subtype C

Abstract

An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vac-cinia virus Ankara (MVA) expressing HIV-1 Env on virus-like particles. In this study, we evaluated whether the addition of a gp120 protein in alum or MVA-expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime-MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26, and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cyto-toxicity (ADCC), and low-titer tier 1B and tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity, and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses, whereas the MVAgp140 boost resulted in improved anti-body durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost, whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly , gp120, but not the MVAgp140 boost, increased peak CD4 T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4 T cell responses. IMPORTANCE Prior immune correlate analyses with humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with re-combinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime-MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4 T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses.

T-Cell Vaccine Strategies for Human Immunodeficiency Virus, the Virus with a Thousand Faces

“…2). While some vaccine designs are based on viral proteins found in particular geographic regions or nations (16,22), others take into consideration not only the regionally circulating viral forms but also regional human population HLA allele frequencies (45,91).…”

Inactivated parapoxvirus ovis activates canine blood phagocytes and T lymphocytes

“…Otherwise attenuated poxviruses have immunogenic properties and induce strong innate host 45 immune response (Burgers et al, 2008;Gherardi and Esteban, 2005), probably due to facilitated cellular uptake by macropinocytosis (Mercer and Helenius, 2008). Parapoxvirus ovis (PPVO) shows a restricted host range for sheep and goats with a tropism to the skin and mucous membranes and lack of systemic virus spread (Büttner and The known immunostimulating properties on the innate immune system combined with a weak and transient immune response to the virus makes PPVO an optimal candidate for an 60 immunoactivator.…”

Recombinant MVA vaccines: dispelling the myths

“…For example, instability of an HIV Env transgene has been reported independently by two groups [37,38]. It is therefore indubitably advisable to confirm transgene stability over ten serial passages in the producer cell line prior to manufacturing (as for recombinant adenoviral vectors [39]).…”