Abstract
Background: A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines.Methods: Env-specific IgG responses were mapped in samples of the UKHVC003 Standard Group (UK003SG, n = 11 from UK) and TaMoVac01 (TMV01, n = 17 from Tanzania) HIV vaccine trials. Both trials consisted of three immunizations with DNA, followed by two boosts with recombinant Modified Vaccinia Virus Ankara (MVA), either mediating secretion of gp120 (UK003SG) or the presentation of cell membrane bound gp150 envelopes (TMV01) from infected cells, and an additional two boosts with 5 μg of CN54gp140 protein adjuvanted with glucopyranosyl lipid adjuvant (GLA). Env immunogen sequences in UK003SG were solely based on the clade C isolate CN54, whereas in TMV01 these were based on clades A, C, B, and CRF01AE. The peptide microarray included 8 globally representative Env sequences, CN54gp140 and the MVA-encoded Env immunogens from both trials, as well as additional peptide variants for hot spots of immune recognition.Results: After the second MVA boost, UK003SG vaccinees almost exclusively targeted linear, non-glycosylated antigenic regions located in the inter-gp120 interface. In contrast, TMV01 recipients most strongly targeted the V2 region and an immunodominant region in gp41. The V3 region was frequently targeted in both trials, with a higher recognition magnitude for diverse antigenic variants observed in the UK003SG (p < 0.0001). After boosting with CN54gp140/GLA, the overall response magnitude increased with a more comparable recognition pattern of antigenic regions and variants between the two trials. Recognition of most immunodominant regions within gp120 remained significantly stronger in UK003SG, whereas V2-region recognition was not boosted in either group.Conclusions: IgG recognition of linear antigenic Env regions differed between the two trials particularly after the second MVA boost. Structural features of the MVA-encoded immunogens, such as secreted, monomeric gp120 vs. membrane-anchored, functional gp150, and differences in prime-boost immunogen sequence variability most probably contributed to these differences. Prime-boosting with multivalent Env immunogens during TMV01 did not improve variant cross-recognition of immunodominant peptide variants in the V3 region.
Highlights
Development of an efficacious vaccine against the Human Immunodeficiency Virus-1 (HIV) is complicated by high variability of the HIV envelope glycoprotein (Env), and by the difficulty to induce broadly cross-reactive neutralizing HIV Envspecific antibody responses [1, 2]
The 11 vaccine recipients from UK003SG included in the analyses were all white Europeans and had a median age of 36 years and included 5 females
Four weeks after the second MVA boost, we observed profound differences in the antigenic regions targeted by the Envspecific IgG response between UK003SG and TMV01 (Figure 3; Table 1)
Summary
Development of an efficacious vaccine against the Human Immunodeficiency Virus-1 (HIV) is complicated by high variability of the HIV envelope glycoprotein (Env), and by the difficulty to induce broadly cross-reactive neutralizing HIV Envspecific antibody responses [1, 2]. Vaccine-induced protection from HIV acquisition may be possible in the absence of a strong HIV neutralizing antibody response; during the Rv144 trial, high IgG levels targeting the Env hypervariable regions 1 and 2 (V1V2) correlated with protection from HIV acquisition [3]. High levels of vaccine-induced Env-binding antibodies—and in particular those targeting the V2 region— correlated with protection from AIDS virus acquisition during a well-controlled non-human primate study [8]. Together these results emphasize that non-neutralizing antibody responses targeting vulnerable Env regions may mediate vaccine-induced immunity. A better understanding of the parameters influencing vaccine-induced IgG recognition of individual antigenic regions and their variants within the HIV Envelope protein (Env) can help to improve design of preventive HIV vaccines
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