|Antigen-specific CD8+ T cell expansion, contraction and generation of memory phenotype by recombinant viral vectors. (Rollier, CS; Reyes-Sandoval, A. et al. Curr. Opin. Immunol. 23(3):377. 2011)|
|Visualisation of P. berghei malaria parasites expressing the reporter gene mCherry (red). Sporozoites are shown on the top panel and schizonts growing in hepatocytes at various times post infection (p.i.) are shown at the lower panel. Photos were taken using fluorescence microscopy.|
|Photomicrograph showing the midgut of an Anopheles mosquito infected with a transgenic Plasmodium parasite expressing green fluorescent protein (GFP). When a mosquito ingests blood of an infected organism, the parasite's gametes fertilize and travel to the midgut epithelium where they form structures known as oocysts (green structures in the micrograph). Inside every oocyst, thousands of sporozoites develop to subsequently travel to the salivary glands, ready to be injected during the next blood meal taken by the mosquito. The fluorescent image in the middle permits a better visualization of the oocysts than the one obtained using light microscopy left. Photo taken by PhD student Ahmed Salman and R.A. Amar Lall.|
The fight against malaria is becoming of central importance in the global health agenda since the initial commitment by the WHO in 1969 to eradicate this disease. Such momentum has been driven by the growing appreciation of the humanitarian and economic problem, novel tools to fight this disease and an increased access to funding organisations.
Of the two malaria parasites with the greatest prevalence, Plasmodium vivax is the most difficult to eliminate from endemic areas because of its ability to remain dormant as hypnozoites in the liver of an infected person for weeks, months or years to later reactivate and continue with the transmission cycle.
The presence of a parasite with the ability to hide for years constitutes a formidable challenge to its elimination from densely populated areas of Asia and Latin America, where it threatens nearly 40% of the human population and is responsible of approximately 132 to 391 million cases of malaria with an overall cost of around US$ 1.2-4.0 billion per year.
There is currently no licensed vaccine for malaria and vaccine development for P. vivax has been particularly a slow process with only two candidates reaching clinical trials and yielding modest results. Fortunately, modern tools and techniques will permit faster progression towards the development of novel vaccine candidates.
In recent years, I have contributed to the development of one of the leading vaccine candidates for P. falciparum malaria that targets the parasite at the liver, where it stops and multiplies before entering the blood (pre-erythrocytic or liver-stage vaccines). This strategy uses novel recombinant viral vectors (ChAd63 and Modified Vaccinia Ankara, MVA) expressing the recombinant antigen TRAP. By exploiting their extraordinary ability to stimulate both arms of the adaptive immune response –antibodies and T cells-, we can elicit immune responses able to provide outstanding protection in a sporozoite challenge that mimics the infection process by which a mosquito inoculates parasites into a mammalian host. My research contributed to the understanding of mechanisms responsible for the extraordinary protective efficacy of recombinant viral vectors, laying the basis for their optimal use as malaria vaccines, including the following examples:
- First description of a single vaccination with chimpanzee adenoviral vectors and its ability to induce complete, sterile protection against a sporozoite challenge using the P. berghei malaria parasite (Eur J Immunol, 2008).
- Demonstration that Ad-MVA prime-boost vaccination regimens elicit long-term protection against malaria and enhance functionality of CD8+ T cells (Infect Immun, 2010).
- Identification of correlates of protection for T-cell-inducing vaccines in pre-erythrocytic malaria (Infect Immun, 2010; J Immunol, 2011).
- Demonstration of the potential of viral-vectored vaccination for pre-erythrocytic malaria in nonhuman primates and humans (Vaccine, 2010; J Infect Dis, 2012).
- Various methods to enhance the immunogenicity and protective efficacy of viral vectors against malaria (Mol Ther, 2012; PLoS One, 2012).
My ongoing research focuses on the development of a novel malaria vaccine against P. vivax using recombinant viral vectors expressing pre-erythrocytic antigens. Through the support of the Wellcome Trust, I will aim to develop and investigate the following:
- A novel P. vivax vaccine using recombinant viral vectors expressing pre-erythrocytic antigens.
- Development of novel transgenic P. berghei parasites expressing P. vivax transgenes that would permit assessment of new vaccine candidates.
- The ability of viral-vectored vaccines to target the hypnozoites from P. vivax.
- Design, production and purification of proteins from P. vivax to be used for research and vaccine development.
An additional research interest consists on the development of vaccines for dengue using recombinant viral vectors.
Recombinant Plasmodium vivax circumsporozoite surface protein allelic variants: antibody recognition by individuals from three communities in the Brazilian Amazon.
Soares IF. et al, (2020), Scientific reports, 10
The importance of the immunodominant CD8+ T cell epitope of Plasmodium berghei circumsporozoite protein in parasite- and vaccine-induced protection.
Gibbins MP. et al, (2020), Infection and immunity
Evaluation of Chimpanzee Adenovirus and MVA Expressing TRAP and CSP from Plasmodium cynomolgi to Prevent Malaria Relapse in Nonhuman Primates.
Kim YC. et al, (2020), Vaccines, 8
Immunogenicity and Efficacy of Zika Virus Envelope Domain III in DNA, Protein, and ChAdOx1 Adenoviral-Vectored Vaccines.
López-Camacho C. et al, (2020), Vaccines, 8
Protective efficacy of peptides from Plasmodium vivax circumsporozoite protein.
Atcheson E. and Reyes-Sandoval A., (2020), Vaccine, 38, 4346 - 4354