HIV-2 and SIV vaccine studies in macaques : with emphasis on humoral immune responses

Abstract

This thesis describes the evaluation of HIV vaccines candidates in the HIV-2 or SIV monkey models. The immunogenicity and protective efficacy of the vaccines were investigated. Furthermore, correlates to protective immunity were sought.

Immunisation with whole inactivated HIV-2 induced varying levels of antibody responses depending on the adjuvant used. Protection against HIV-2 infection was seen in 7/21 vaccinees. An increase in the number of immunisations did not necessarily enhance vaccine efficacy. The antibody reponses induced by an envelope subunit HIV-2 vaccine given in either Ribi's adjuvant or in immunostimulating complexes (ISCOMS) were studied in detail. High antibody titres were detected already after two immunisations with HIV-2 gp125 in ISCOMS and only minor increases were detected thereafter. In contrast, four or five immunisations with HIV-2 gp125 in Ribi were needed to reach equivalent levels. Four of ten vaccinees were protected against intravenous HIV-2 challenge. These monkeys also exhibited reduced viral replication after heterologous intrarectal SIVsm challenge.

Vaccination with a live attenuated SIV vaccine (SIVmacC8) induced both humoral and cell mediated immune responses. The difficulty of inducing sterilising immunity even with an attenuated vaccine was shown when protection was induced against intrarectal SIVsm challenge in a proportion of the vaccinees but not against the more divergent HIV-2 given intravenously.

Attenuated retroviral vaccines may not be used in man due to safety concerns, therefore other vaccine strategies were sought. Modified vaccinia virus Ankara that expressed SIV structural proteins (MVA-SIVsm) or structural and regulatory antigens (MVA-SIVmac) was used. The MVA vaccines were given alone, in combination with a protein boost in ISCOMs or in combination with another viral vector, Semliki Forest virus, expressing the same antigens. High levels of binding antibodies were induced by the prime-boost protocols. Furthermore, neutralising antibodies were also induced. The potential of combining immunogens to enhance selected immune responses was emphasised when the induction of cell mediated immune responses was investigated. The combination of MVA-SIVsm with a protein boost induced very strong T-cell proliferative responses but, generally, no cytotoxic T-lymphocytes (CTLs). The combination of SFV-SIVmac and MVA-SIVmac vaccines induced broad CTL responses but, by comparison, weaker T-cell proliferative responses.

Protection was elicited in a proportion of the monkeys. Yet, no single immune correlate could be defined by the immune parameters used in these studies. Our studies indicate that to elicit protective immunity both potent humoral and cell mediated immune responses may be needed.

These investigations show that the choice of adjuvant in vaccine formulations is important and the use of prime boost protocols may determine the immune responses elicited by a specific immunogen. Such strategies can be used in future vaccine studies to enhance desired immune responses once the immune correlates to protection against HIV and AIDS have been established.