Streamlining Heterologous DNA-Prime and NYVAC/Protein-Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens.

Publication Type:

Journal Article

Source:

Journal of virology (2016)

Abstract:

In follow up to the modest efficacy observed in the RV144 trial, the HIV vaccine field seeks to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc 01 - 03) evaluated the immunogenicity of HIV-1 C-clade GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C-priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses as compared to NYVAC-C alone. Moreover, responses were improved using three as opposed to two DNA-C primes. Here, we assessed in non-human primates whether such vaccination regimens can be further streamlined using fewer and accelerated immunizations when employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C + protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well balanced CD8+ and CD4+ T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial ADCC and modest ADCVI activities, but very low neutralization activity were measured after final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth and quality as compared to earlier generation EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination especially in resource-constrained settings.

IMPORTANCE: Within the EuroVacc clinical trials we previously assessed the immunogenicity of HIV C-clade antigens delivered in a DNA-prime/NYVAC-boost regimen. The trials showed that the DNA prime crucially improved the responses and three DNA primes with NYVAC-boost appeared optimal. Nevertheless, T cell responses were primarily Env-directed and humoral responses modest. The aim of this study was to assess improved antigens for their capacity to elicit more potent and balanced responses in rhesus macaques even when using various simpler immunization regimens. Our results showed that the novel antigens in fact elicited higher numbers of T cells with a polyfunctional profile and good Env:GagPolNef-balance, as well as high titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.