Breakthrough in developing the PD-1-enhanced DNA vaccine for over 6-year cART-free AIDS prevention and virologic control

The study also found that polyfunctional and broadly reactive effector-memory virus-specific T cells were maintained in the protected experimental macaques for over six years. The findings provide supporting evidence that the PD-1-enhanced DNA vaccine strategy holds promise as a third-generation DNA vaccine for AIDS prevention and immunotherapy. The peer-reviewed study was published in the journal Microbiology Spectrum, by The American Society for Microbiology.

Background

Using cART for both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) contributes efficiently to reducing AIDS-related deaths and HIV-1 transmission cases. Despite the effectiveness of cART, HIV-1 can persist in latent reservoirs. This has made it challenging to achieve complete or sustained cART-free virologic control of HIV-1 infection for the past 40 years since the discovery of AIDS and its causative agent HIV-1 in the early 1980s. Moreover, the extensive HIV-1 genetic diversity facilitates the formation of mutational escape variants that resist cART drugs, resulting in the clinical failure of viral control. The huge number of viral variants also hampers AIDS vaccine development. Identifying novel vaccination strategies, including the induction of robust cross-reactive T cell responses, will enhance the arsenal against HIV/ AIDS epidemic.

Research methods and findings

The researchers developed a vaccine technology known as the programmed death-1 (PD-1)-enhanced DNA vaccine strategy, which involves using a DNA vector to encode specific antigens fused with the soluble domain of PD-1 protein. Our previous murine studies found that this strategy allows more efficient antigen delivery targeting to professional antigen-presenting cells, called dendritic cells. It results in the superiority of immunogenicity and the protective efficacy against both viral infection and tumorigenesis over conventional vaccines. Notably, PD-1-enhanced DNA vaccines elicit strong CD8+ T cell responses.

In 2021, the researchers reported the findings of a rhesus monkey study, which evaluated the potential of a PD-1-enhanced DNA vaccine against the simian -- human immunodeficiency virus (SHIV). The rhesus monkeys were vaccinated with a DNA vaccine, pRhPD1-p27, designed based on the PD-1-enhanced DNA vaccine strategy. The vaccine resulted in sustained virological control against pathogenic SHIVSF162P3CN challenge, which was mediated by a strong polyfunctional vaccine-induced effector-memory CD8+ T cell response. In a group of four pRhPD1-p27-vaccinated macaques, an aviremic state (absence of detectable virus in the blood) was maintained for two years, indicating that potential cART-free virologic control could be achievable with the PD-1-enhanced DNA vaccine. The recent follow-up study demonstrated extended cART-free virologic control for over six years.

Efficient strategies for HIV-1 cART-free virologic control are crucial for ending the AIDS epidemic. 'Our innovative PD-1-enhanced DNA vaccine was effective not only in inducing polyfunctional effector-memory CD8+ T cells for AIDS prevention in rhesus monkeys, but also in sustaining cART-free virologic control for over six years,' remarked Professor Chen Zhiwei, Director of the AIDS Institute and Chair Professor of the Department of Microbiology, School of Clinical Medicine, HKUMed, who led the study. 'The encouraging outcomes validate the continuation of ongoing clinical trials investigating the potential of the PD-1-enhanced DNA vaccine for achieving HIV-1 cART-free virologic control. Hopefully, the vaccine can be employed independently or in conjunction with other biomedical interventions for individuals living with the virus in the future.'

If this efficacy can be replicated in humans, a therapeutic vaccine for cART-free HIV-1 control will be on the horizon. Currently, a Phase I clinical trial, in which the HKUMed team is collaborating with The Third People's Hospital of Shenzhen to test whether the non-human primate data can be replicated in humans, is underway. The report of the trial results is expected to be available in the second quarter this year.