A vaccine is a protein, cell wall, or an attenuated or a killed microbe that is immunogenic but not pathogenic, i.e., able to elicit an immune response but not able to cause disease. Since the discovery of the first vaccine by Edward Jenner in 1796, vaccines have undergone a long span of evolution. The journey of the vaccines started from a weak microbe to the outer coat/cell wall of bacteria to the purified proteins to the recombinant DNA vaccines. The delivery methods of the vaccines are also diverse, they can be given as an oral drop, or by nasal application, or can be injected intramuscularly.
The absolute control of smallpox disease is living proof of the potency of the vaccines. Despite the applauding success of the vaccines, there are a number of diseases that are still waiting for a suitable vaccine. The list includes epidemiologically important diseases such as, malaria that accounts for nearly 3.5 million cases and 1000 deaths per annum. The development of resistance to anti-malarial drugs has only worsened the situation.
The major hurdle in the vaccine discovery is the high mutation rate of the surface proteins of the pathogens. The Plasmodium parasite undergoes six transition states and has two alternative hosts. The vaccines can be developed for the blood-stage parasites like merozoites or sporozoites. Antigenic diversity of the vaccine candidate proteins is a big hurdle in the vaccine development process. The high mutation rate in the candidate molecules further complicates the problem.
The recombinant DNA technology brought hope for vaccine development. The genes encoding various vaccine candidates of Plasmodium were expressed together along with different adjuvant molecules to create a vaccine.
A pre-erythrocytic vaccine RTS, S is so far the most promising vaccine that reached the Phase 3 trial. The vaccine was well tolerated in children and four doses of the vaccines reduced malaria by 39% in 5-17-month-old children. However, the vaccine was ineffective for infants.
The transmission of malaria involves female Anopheles mosquitoes. Along with the blood, the female Anopheles ingests male and female gametocytes of the Plasmodium parasite, which in mosquito midgut transforms into mature gametes and fuse to form a zygote. The zygote elongates to form ookinete that traverses the mosquito midgut and transform into an oocyst. The oocysts burst to release infective sporozoites, which travels to salivary glands. The next blood meal of the mosquito would inject the infective sporozoites into a healthy person. The malaria parasite feeds on the mosquito cells and thus the mosquito’s immune response tries to ward off the developing parasite.
Researchers are looking for a type of vaccine, termed transmission-blocking vaccine. The transmission cycle of malaria can be blocked either by killing sexual stages of parasites; or by feeding antibodies synthesized against midgut or salivary glands or both; or by manipulating the midgut microbiota of the mosquitoes.
A transmission-blocking vaccine (TBV) is a vaccine that targets the sexual stages of the malaria parasite and thus, prevents its transmission through a community. The TBV would reduce morbidity and mortality due to malaria. The sexual stages that can be targeted include gametocytes, gametes, and ookinetes. The success of TBV is a factor of its ability to induce high antibody titers to efficiently block the malaria cycle. The putative candidates for a potential TBV are the surface proteins (antigens) of the malaria parasites, Plasmodium falciparum, and P. vivax. Pfs230, Pfs48/45, and Pfs25 are potential TBV candidates of P. falciparum, while Pvs25 is the most suited TBV target antigen of P. vivax. Pfs25 and Pvs25 are the most effective TBV target antigens and have been recombinantly expressed in various heterologous hosts such as yeasts (Saccharomyces cerevisiae and Pichia pastoris) and E.coli. The phase I clinical trial with Pfs25 and Pvs25 was deemed safe for humans.
In addition to the Plasmodium derived molecules, antibodies raised against the midgut proteins of Anopheles gambiae and Phlebotomus papatasi were found to detrimental to the developing parasite in these vectors. These proteins are also seen as potential TBV candidates.
The TBVs seems to be an important alternative to the routine vaccines because:
- TBVs lead to no or negligible immune enhancement of infectivity that may have prevented the vaccine development.
- The antigenic diversity of the vaccine candidates is not a problem in the way of the TBV development.
- In the mosquito host, the immune-responsiveness is not a problem for key antigens.
Dr. Anil Sharma is founder director of AAiM Edupoint, a data analysis, and editing service provider Company. He has research experience of more than 18 years in the field of Molecular Entomology, Vector-Borne Disease Biology and Genetic Engineering. After completing his Ph.D.on insect immunity from National Institute of Malaria Research, New Delhi, he joined International Centre for Genetic Engineering and Biotechnology, New Delhi and continued his work on insect biology and extended the work to the biology of malaria and chikungunya parasites. At present, he is managing AAiM Edupoint and is serving as a General Secretary of a non-profit society, Biological Innovations Research Development Society.