Date Published: September 12, 2017
Publisher: BioMed Central
Author(s): C. Yong Kang, Yong Gao.
The development of an efficient prophylactic HIV vaccine has been one of the major challenges in infectious disease research during the last three decades. Here, we present a mini review on strategies employed for the development of HIV vaccines with an emphasis on a well-established vaccine technology, the killed whole-virus vaccine approach. Recently, we reported an evaluation of the safety and the immunogenicity of a genetically modified and killed whole-HIV-1 vaccine designated as SAV001 . HIV-1 Clade B NL4-3 was genetically modified by deleting the nef and vpu genes and substituting the coding sequence of the Env signal peptide with that of honeybee melittin to produce an avirulent and replication efficient HIV-1. This genetically modified virus (gmHIV-1NL4-3) was propagated in a human T cell line followed by virus purification and inactivation by aldrithiol-2 and γ-irradiation. We found that SAV001 was well tolerated with no serious adverse events. HIV-1NL4-3-specific polymerase chain reaction showed no evidence of vaccine virus replication in participants receiving SAV001 and in human T cells infected in vitro. Furthermore, SAV001 with an adjuvant significantly increased the antibody response to HIV-1 structural proteins. Moreover, antibodies in the plasma from these vaccinations neutralized tier I and tier II of HIV-1 B, A, and D subtypes. These results indicated that the killed whole-HIV vaccine is safe and may trigger appropriate immune responses to prevent HIV infection. Utilization of this killed whole-HIV vaccine strategy may pave the way to develop an effective HIV vaccine.
Despite proactive HIV/AIDS education and availability of effective combination antiretroviral therapy (cART), the AIDS pandemic continues. WHO and UNAIDS estimate that close to 37 million people are currently living with HIV infection and approximately 40 million HIV related deaths have occurred since the discovery of HIV-1 . However, vaccine development against HIV continues to struggle due to unresolved questions on the exact components of the human immune response that confer protection against HIV infection. Similar to multiple effective anti-viral vaccines, a safe, effective, and globally accessible HIV vaccine must be developed to end the AIDS pandemic.
The first human clinical trial of Vaxgen’s AIDSVAX was based on a recombinant HIV-1 gp120. This trial showed that 5.7% of 3330 vaccinated high-risk volunteers contracted HIV while 5.8% of the 1679 placebo control group contracted HIV . The monomeric form of recombinant gp120 induced antibodies but failed to neutralize the virus. We now know that the native conformational epitopes of the trimeric form of gp120 are key to generating neutralizing antibodies [4, 5].
There are three types of commercially available vaccines. These include attenuated live virus vaccines, recombinant protein based subunit vaccines, and killed whole-virus vaccines. Although there have been many successful live attenuated viral vaccines developed against many human and animal viral diseases, the attenuated live virus vaccine strategy is not an option for HIV, because the proviral DNA of live attenuated HIV will be integrated into the host chromosomal DNA to establish a persistent infection.
The killed whole-HIV-1 vaccine approach has great merit as it has the potential to present multiple viral antigens to the immune system in their native conformation. Thus, two groups have suggested that it is time for another look at inactivated (killed) HIV vaccine for prevention of HIV infection [21, 22]. The challenges in developing a killed whole-HIV vaccine include the lack of techniques for high level virus production and the safety issues associated with virus production in large quantities. We overcame these problems by deleting the nef gene which contributes to AIDS pathogenesis [23–26] and substituting the envelope glycoprotein signal peptide gene to achieve high level virus replication [27, 28].
The major concern for the killed whole-HIV vaccine is the incomplete inactivation of HIV. One viable HIV virion during the virus inactivation process is indeed one too many for a killed whole-virus vaccine. To ensure the safety of the vaccine, we deleted the nef gene for attenuation, and used both chemical (aldrithiol-2) and physical (γ-irradiation) inactivation to provide complete killing. The test for in vitro replication of SAV001 using sensitive methods showed that virus replication was absent even after ten consecutive passages in human T lymphocytes .
Despite the complete inactivation of gmHIV-1NL4-3 virus used in our study, we only enrolled HIV-1 positive asymptomatic volunteers based on discussions with the US FDA. Therefore, even though the study was designed to evaluate safety and tolerability, the nature of the study limited our ability to assess the immunogenicity of the vaccine formulations. Previous studies have shown that HIV-1 infection elicits antibody responses to proteins encoded by HIV-1 gag, pol and env genes, and the antibody response to various proteins appears at different stages of infections . As expected, most of the subjects in our study had a high baseline antibody titer against viral structural proteins. However, with a single SAV001 intramuscular vaccination, the humoral immune response was significantly increased by boosting the secondary anti-HIV antibody responses in vaccinated groups suggesting a strong immunogenicity of the SAV001 vaccine.
Vaccination with SAV001, the genetically modified and killed whole-HIV-1 vaccine, could enhance humoral immune responses including broadly neutralizing antibody production in HIV-negative individuals. Therefore, SAV001 represents a promising starting point for the development of a safe and effective prophylactic HIV-1 vaccine using the killed whole virus approach. This approach could be easily adaptable to include different subtypes of HIV-1.