Adenovirus prime, Env protein boost vaccine protects against neutralization-resistant SIVsmE660 variants in rhesus monkeys

Abstract

Previous studies have shown that DNA prime, Ad5 boost vaccines protect against neutralization-sensitive but not neutralization-resistant virus variants within the SIVsmE660 swarm. Here we show that Ad prime, Env protein boost vaccines protect against neutralization-resistant SIVsmE660 variants. We perform two studies in rhesus monkeys with Ad35/Ad26 vectors expressing SIVmac239 Gag/Pol/Env with or without an AS01B-adjuvanted SIVmac32H gp140 protein boost. In a repetitive, low-dose challenge study, we observe robust protection against acquisition of infection by both Ad Alone and Ad/Env vaccines. In a single, high-dose challenge study, only the Ad/Env vaccine affords significant protection against acquisition of infection. Analysis of transmitted/founder (T/F) viruses from this study demonstrates that the Ad/Env vaccine blocks both neutralization-sensitive and neutralization-resistant SIVsmE660 variants in rhesus monkeys with restrictive TRIM5α alleles. These data demonstrate that the adjuvanted Env protein boost is critical for protecting against high-dose SIVsmE660 challenge and for blocking neutralization-resistant viruses within the SIVsmE660 swarm.

Control of Heterologous Simian Immunodeficiency Virus SIV smE660 Infection by DNA and Protein Coimmunization Regimens Combined with Different Toll-Like-Receptor-4-Based Adjuvants in Macaques

“…Despite these differences, none of those features could be linked to better protective responses between the two vaccine groups. TRIM-5α R animals in both groups showed a decreased risk of virus acquisition due to the vaccine, in agreement with data from other reports ( 31 , 54 – 56 ). We found that both TRIM-5α R and M/S animals with mucosal V1V2 Ab showed a significantly decreased risk of virus acquisition due to the vaccine, and the vaccine effect was stronger in the TRIM-5α R animals.…”

“…Here, we found that vaccines formulated with both TLR4+7 and TLR4+QS21 adjuvants induced robust and durable antibody responses that efficiently disseminated to mucosal surfaces and delayed SIV smE660 acquisition in macaques carrying TRIM5-α-restrictive alleles, and in addition, the vaccine-induced humoral and cellular immune responses help to control acute and chronic viremia in immunized animals. Thus, as noted by others, the TRIM-5α-resistant allele influences the rate of viral acquisition ( 50 – 55 ), and this effect is increased in vaccinated macaques ( 31 , 41 , 46 , 54 – 56 ). In agreement with those reports, we also found that the TRIM-5α genotype acts as a confounding contributor, together with cross-clade SIV smE660 -specific NAb and mucosal V1V2 bAb, to vaccine-induced control of SIV smE660 acquisition.…”

“…Using a DNA-adenovirus type 5 (Ad5) vaccine, protection against a neutralization-sensitive T/R variant and a sieve effect resulting in a significant overrepresentation of neutralization-resistant A/K SIV smE660 were reported ( 54 ). Using an Ad prime-Env protein boost vaccine, protection against the neutralization-sensitive T/R SIV smE660 was recently reported; however, due to the low number of infected animals, no clear sieve effect could be established ( 55 ). Thus, the study presented here comparing T/F variants of vaccinees and controls and other studies ( 54 ) clearly showed that A/K virus selection is linked to a vaccine-induced protective mechanism and not to innate selection, since the controls and the challenge stock show the same frequency of A/K virus variants.…”

“…Tripartite-motif-containing protein 5 alpha (TRIM-5α) ( 47 – 49 ) is a potent innate restriction factor which affects SIV smE660 infection ( 50 – 53 ), exerting its function via interaction with the incoming virus particles, in particular with the viral capsid protein, a proteolytic Gag-processing product, and it was shown that mutations in two sites (P37S and R98S) in the capsid protein could alleviate this antiviral effect ( 52 ). The TRIM-5α-resistant (TRIM-5α R) allele as an innate protective immune mechanism can assist vaccine-induced immune responses in controlling infection ( 31 , 54 – 56 ). Balancing the groups, we also addressed the contribution of the TRIM-5α genotype in our study.…”

Progress in Adenoviral Capsid-Display Vaccines

“…For some complex pathogens, effective vaccine-mediated protection requires potent multifaceted B- and T-cell immune responses [ 21 , 22 ]. This can be achieved using a prime-boost vaccination approach with, for example, an AdV prime and adjuvanted recombinant protein boost, containing the same antigens [ 23 , 24 , 25 , 26 ].…”