Vaccine design to kick immune response into high gear

Clive Michelo is a SANTHE Post-doctoral Trainee based at the Centre for Family Health Research in Zambia (CFHRZ) of the Rwanda Zambia HIV Research Group in Lusaka, Zambia. SANTHE (Sub-Saharan African Network for TB/HIV Research Excellence) is one of the eleven Developing Excellence, Leadership, and Training in Science in Africa (DELTAS Africa) programmes. DELTAS Africa funds Africa-based scientists to amplify the development of world-class research and scientific leadership on the continent while strengthening African institutions. DELTAS Africa is implemented through the AESA Platform. AESA (The Alliance for Accelerating Excellence in Science in Africa) is a funding, agenda-setting, programme management initiative of the African Academy of Sciences (AAS), the African Union Development Agency (AUDA-NEPAD), founding and funding global partners, and through a resolution of the summit of African Union Heads of Governments. DELTAS Africa is supported by Wellcome and the United Kingdom Foreign, Commonwealth and Development Office (FCDO formerly DFID).

Summary

The current WHO guidelines strongly recommend initiation of antiretroviral therapy (ART) as soon as possible after diagnosis, as this has been associated with significant improvements in clinical outcome. However, in resource-limited settings, accessibility and number of people on ART imposes a major financial burden on patient, their families and local healthcare systems. Therefore, more cost-effective alternatives to mitigate the far reaching economic and social consequences of lifelong ART are needed.

Human Immunodeficiency Virus type 1 (HIV-1) is responsible for the majority of HIV infections around the world and is behind the Acquired Immunodeficiency Syndrome (AIDS) epidemic as a result of the severe damage it can cause to a person’s immune system. AIDS is the most advanced stage of the HIV infection and is transmitted through direct contact with HIV-infected body fluids, such as semen, vaginal fluids and blood, or from an infected mother to her child during pregnancy, delivery or breastfeeding.

For the past two decades, advances in ART have transformed HIV-1 infection from a fatal disease into a chronic medical condition that in many instances does not compromise the quality of life. However, ART continues to have limitations; because of these, the theoretical ability of ART to extend life expectancy to normal levels has not been realized in many cases. Strategies to address these limitations are a subject of active ongoing research; an effective HIV-1 vaccine is considered to be the best way to end the HIV-1 pandemic.

Alleviating the HIV-1 burden through a preventive and curative vaccine

Clive Michelo’s team hopes to alleviate the continued public health and economic burden that HIV-1 has placed not only on the health care system, but on society as a whole. A preventive and curative vaccine is currently the only cost-effective approach to effectively deal with the pandemic.

The use of ART has resulted in prolonged lifespan and improved quality of life. ART controls the presence of the virus in blood cells in most HIV infected individuals. However, individuals on ART require lifelong adherence, and withdrawal of therapeutic regimens inevitably lead to the rebound of the virus. This is because ART is directed against replicating HIV infected cells and not cells carrying latent HIV reservoirs, rendering ART ineffective as an HIV cure. Notwithstanding the effectiveness of ART, there is incomplete suppression of the virus with notable spikes in the amounts of virus in the blood, even in individuals who adhere to treatment.

This project explores vaccine design approaches that elicit robust adaptive immunity T-cell-based responses. One of the major challenges of HIV-1 vaccine development is its global diversity, making it particularly difficult to come up with just one vaccine that can work on different HIV-1 strains from different regions of the world. Hence, we are currently trying a more targeted approach by using viruses isolated from a local target population in the vaccine design pipeline in order to develop a vaccine that is more effective for that population.

 Methods

All blood samples and virus isolates were collected from the same population but under different study protocols sponsored by the International AIDS Vaccine Initiative (IAVI). Samples from the same population were used in an attempt to develop more efficient processes for identification of immunogens that can be linked to virus control and could contribute to vaccine design within that population. All samples were collected with written, informed donor consent. The protocols included sampling of healthy HIV-1 uninfected participants and sampling of 32 HIV-1-infected participants at approximately 365 days post Estimated Date of Infection (EDI). The HIV-1 positive participants were part of an IAVI-sponsored Protocol C study cohort in which over 3,000 plasma and PBMC samples from 286 Zambian participants were collected at the Centre for Family Health Research in Zambia (CFHRZ) laboratories. Protocol C was a prospective, observational, multi-centre study conducted between February 2006 and December 2011 to evaluate laboratory, clinical, immunological and viral markers of disease progression in recently HIV-infected volunteers.

Results

Our results so far indicate that the approach to the identification of HIV-1 specific immunogens using immune cells and virus isolates from cohorts within the same defined population can provide a novel platform for better evaluation of immune cell responses that are potentially relevant for protection against circulating viruses and which could be exploited for vaccine development within that population.

Challenges

The dynamic research and learning landscape are aspects of science that I love. My project is motivated not just by the intellectual engagement that it offers, but also by its relevance to disease with huge public health and economic implications not just for me, but for my friends, family, neighbours and the rest of the world. Reflecting on this makes me feel relevant and actualised.

The challenges I experienced were not a setback: they are a hallmark of research. This is because a researcher’s work consists not only of answering unanswered questions, but also of developing relevant new questions. The main challenge I have faced in my work has been dealing with results that were not anticipated. Such developments represent unchartered territories in research from which unexpected discoveries can be made. Every bit of knowledge gained in our attempt to develop an efficacious vaccine provides further insight to achieving our goal of a world without HIV.