In 2021, 38.4 million people were living with HIV and 650,000 died. No cure currently exists and much of the management of HIV in infected patients involves antiretroviral therapy (ART). ART’s have significantly improved over recent years and when used chronically, can allow HIV patients to safely live with the disease. However, patients need to strictly adhere to treatment and recent data indicates that “HIV survivors” on chronic ART may have elevated risk of cardiovascular disease.
The ultimate goal in combating HIV and AIDS is the development of a potent vaccine. The proposed correlates of protection from HIV infection include neutralizing antibodies (nAb’s) which target the HIV envelope glycoprotein epitopes as well as antibody-dependent cellular cytotoxicity (ADCC). The difficulty is that the envelope protein is highly glycosylated and is therefore highly modifiable through viral mutations. Rapid viral mutation and the resulting heterogeneity of HIV remain the primary reasons why the development of an HIV vaccine has been so challenging.
The observance of “elite controllers” (infected individuals who live with HIV for years without immune damage with viral loads under 200 copies) holds promise that a humoral response to the virus is possible to successfully eliminate infection. It is theorised that elite controllers possess significant virus-specific T-cell mediated responses.
A successful vaccine needs to:
- Target multiple envelope glycoprotein epitopes
- Elicit a broad nAb immune response
- Target T-cell epitopes on other viral proteins to promote a CD8+ T-cell mediated response
The development of an HIV vaccine started with the AIDSVAX vaccine trial in 2003. Unfortunately, data demonstrated no improved protection from the vaccine candidate based on the gp120 surface glycoprotein. Subsequent trials have used adenovirus vectors to deliver HIV proteins which in some early trials, surprisingly led to increased rates of infection. It is now believed that prior exposure to the adenoviral vector, Ad5, and pre-existing immunity causes immune complexes which could enhance HIV replication in CD4 T-cells. Additionally, Ad5-specific CD4 cells may be more susceptible to infection. A more recent approach aims to stimulate humoral and cellular immunity with so-called “prime boost” vaccines. This approach demonstrated a moderate reduction in risk, likely attributed to facilitation of a greater level of ADCC and broader antibody specificity.
Recently trials of the prime boost vaccine in Southern Africa did not show efficacy and the trials were suspended early. It is thought that the number of different viral strains present in the South African population overwhelmed the immune response. The Mosaico trial is currently ongoing with results expected in 2024. It is a prime vaccine based on an adenovirus vector which delivers several HIV envelopes and internal proteins derived from four different HIV subtypes. Whilst there is optimism for the outcome of this trial, the history of similar vaccines continues to raise concern over improved efficacy.
mRNA technology holds significant promise for HIV vaccine therapy. The COVID pandemic demonstrated just how effective mRNA-based vaccines can be and the number of mRNA vaccine candidates has rapidly increased since 2020. Several preclinical studies using HIV mRNA vaccines have demonstrated neutralising and ADCC activity. A candidate mRNA vaccine developed by the International AIDS Vaccine Initiative, in collaboration with Moderna, is currently in phase 1. The vaccine was designed to target naïve B-cells to produce broad nAb’s.
History has shown a long and challenging battle to combat the AIDS epidemic, which since its beginning, has infected at least 84.2 million people and at least 40.1 million have died (WHO 2021 statistics). ART has greatly improved and has seen widespread application thanks to significant investment from various governments. A vaccine is the primary goal and with limited success with previous technologies, perhaps mRNA technology is the light at the end of the tunnel.
Synexa Life Sciences started in Cape Town, South Africa, where the burden of HIV remains the highest worldwide. Our vision is improving the quality of human health and we are passionate about partnering with clients who are similarly determined to combat disease. Many of our scientists have their scientific foundations in HIV research and our labs are uniquely suited to provide support for vaccine studies. This includes functional flow cytometry to measure cell-specific immune response, soluble biomarker analysis, quantification of the humoral response using ELISA and MSD platforms and pharmacogenetics analysis to quantify vector and virus alike.
Article written by Nicholas Woudberg PhD, Head of Scientific Strategies at Synexa
References
- Buchbinder et al. Lancet. 396: 10260: E68-E69
- 2021. The Search for an HIV prevention vaccine. www.aidsmap.com
- Gray et al. NEJM. 1089-1100
- Matarazzo and Bettencourt. Front Immunol. 14:1172691
