Prevention of HIV infection with a vaccine based on the HIV-1 Tat protein and Tat/Env complex.
The strategies used so far to develop an effective vaccine against HIV/AIDS have been based on proteins from the virus coating (envelope, Env), with the aim of inducing neutralizing antibodies capable of blocking the virus entry into host cells. These approaches have failed due to the high viral protein variability, particularly for Env. CNAIDS is engaged in the development of new preventive vaccines, aimed at inducing an immunity capable of blocking infection and based on the key role played by Tat and the Tat/Env complex in viral infection.
The inexorable spread of HIV infection with over 37 million people infected worldwide (UNAIDS Report on the global AIDS epidemics, 2018) and the increasing number of deaths from AIDS, particularly in developing countries, highlight the urgent need to develop a safe and effective preventive vaccine. The vaccine approaches studied in the last 30 years to block HIV-1 infection mainly target, or targeted, HIV structural proteins and, almost exclusively, those of the outer coating (Env), with the aim of inducing a so-called sterilizing immunity that should be capable of preventing virus entry into the target cell. However, the extreme Env variability not only in different geographical areas, but also from individual to individual and in the same individual over time, is the reason of the substantial failure of these approaches.
Based on these premises, studies conducted by CNAIDS on in vitro mechanisms of infection and in the model of non-human primates (macaca fascicularis) showed that the Tat vaccine is safe and immunogenic (i.e. capable of inducing a specific immune response), and that it is capable of blocking both virus replication and propagation from the entry site, and disease development.
Based on these data, ISS sponsored and conducted two phase-1 preventive clinical trials with Tat protein alone or in combination with the Env protein. The first clinical trial (ISS P-001), which was aimed at assessing the safety and immunogenicity of the Tat vaccine, was conducted and completed in 20 healthy volunteers not at risk of infection, enrolled in 4 Italian clinical centers (San Raffaele in Milan, San Gallicano, Spallanzani and Policlinico Umberto I in Rome). The results obtained indicate full achievement of the primary (safety) and secondary (immunogenicity) objectives of Tat vaccine, confirming that it could proceed to the next stages of clinical development. The second clinical trial (ISS P-002) was conducted in 11 healthy volunteers at risk of HIV infection, enrolled at 3 Italian clinical centers (Policlinico di Modena, IFO-S. Gallicano di Roma and Azienda Ospedaliera S. Gerardo di Monza). The study was aimed at assessing the safety and immunogenicity of the Tat/Env combined vaccine. The results indicated that this vaccine combination is also safe and immunogenic.
Upon obtainment of additional funding, the clinical development of these preventive vaccine approaches will be continued in healthy individuals at risk of infection in countries with high incidence of infection (South Africa), in order to evaluate the effectiveness of the Tat vaccine alone or in combination with the Env protein in preventing HIV infection.