HIV-1 gp120 and Modified Vaccinia Virus Ankara (MVA) gp140 Boost Immunogens Increase Immunogenicity of a DNA/MVA HIV-1 Vaccine

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 vaccinia 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 cytotoxicity (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 antibody 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 recombinant 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.

Vaccine Induction of Heterologous Tier 2 HIV-1 Neutralizing Antibodies in Animal Models

“…Peptide arrays were performed with 1:50-diluted serum samples as previously described (Shen et al, 2017). See Supplemental experimental procedures for further details.…”

HIV/AIDS Vaccines: 2018

“…The gp160, a transmembrane protein, undergoes denaturation when purified and is sufficiently toxic to eukaryotic cells to not be stable in viral vectors. However, when expressed by DNA it primes heterologous tier 1 nAb as well as mostly transient tier 1b and tier 2 nAbs . The binding Ab response to gp160 is largely to gp41, including the immunodominant region (IDR) of gp41, a highly conserved target for pnnAb activities .…”

“…However, depending on the Env, the truncation can reduce the integrity of the receptor binding form of Env . Like gp160, gp150 elicits heterologous tier 1 nAbs and low titer, but frequently transient, tier 1b and tier 2 nAbs . In addition, like the gp160 native form of Env, the predominant binding Ab elicited by gp150 is to gp41 and the highly conserved IDR of gp41.…”

“…Most gp120s do not elicit much V1V2 binding Ab (for example, see Ref. ). However, gp120 does consistently elicit Abs to the C1 region of Env, which is a target for ADCC .…”

“…However, when expressed by DNA it primes heterologous tier 1 nAb as well as mostly transient tier 1b and tier 2 nAbs. 41,42 The binding Ab response to gp160 is largely to gp41, including the immunodominant region (IDR) of gp41, 43 a highly conserved target for pnnAb activities. [44][45][46] The IDR is a desirable target because it does not readily survive mutations that might support escape.…”