Morten A. Nielsen, PhD, on a Potential Malaria Vaccine
A new vaccine against malaria was found to be safe and effective in a new phase 1 trial.1
The trial was conducted in 2 centers—one in Germany and one in Benin—and included 36 volunteers who received either 20 µg (n=9) or 50 µg (n=27) of the vaccine candidate. PAMVAC, the vaccine candidate, was based on a recombinant fragment of VAR2CSA, the Plasmodium falciparum protein responsible for binding to the placenta via chondroitin sulfate A.
Volunteers were randomly assigned to receive PAMVAC adjuvanted with alhydrogel, GLA-SE, or GLA-LSQ 3 times at 4-week intervals.
Results showed that all formulations of PAMVAC were safe and well tolerated. Overall, 262 adverse events occurred, with only 94 being potentially related to the vaccine.
The research team was led by Morten A. Nielsen, PhD, who is an associate professor in the Department of Immunology and Microbiology at the University of Copenhagen in Denmark. Infectious Diseases Consultant caught up with Dr Nielsen to find out more about their study.
ID CON: Malaria in pregnant women has major impacts on the mother’s and child’s health, especially in endemic areas such as sub-Saharan Africa. In your opinion, do you think that having a widely available vaccine against malaria would adequately prevent malaria? Or do you think women in these areas experience vaccine hesitancy?
Morten Neilsen: There will be populations in sub-Saharan Africa where vaccine hesitancy is an issue. However, statements for sub-Saharan Africa as a whole cannot be made. Solutions and implementation will also differ from culture to culture within countries. We hypothesize that implementation of a placental malaria vaccine will follow the trail as rolling out the human papillomavirus (HPV) vaccine in African countries, but this depends on vaccine efficacy and number of doses needed.
ID CON: One potential challenge in this population might be fear of adverse events. The population in your study experienced 94 adverse events potentially related to the vaccine. Can you tell us more about the adverse events experienced by the study cohort?
MN: Fear of adverse events is an issue of utmost importance when rolling out vaccination regimens. For our PAMVAC vaccine, the first safety data were highly satisfactory. The adverse events were comparable with vaccines that are currently used in millions of individuals worldwide, such the influenza vaccine. In fact, the most adverse events were found in the alhydrogel group, which has been used for many years. The next line of clinical trials will test whether the vaccine is safe in studies with larger sample sizes, where more rare incidents may be elucidated.
ID CON: Your findings also stated “In contrast to preclinical findings in rodents and rabbits demonstrating induction of high levels of antibodies using GLA-LSQ compared to alhydrogel or GLA-SE, we found that PAMVAC formulated with GLA-LSQ did not improve immunogenicity compared to GLA-SE.” In the context of efficacy, what might this finding mean for long-term results?
MN: It is often found that adjuvants can activate the immune system differentially in different species. It is also often found that small animals mount very high responses, whereas the same level is difficult to obtain in humans. The reason for this is multifactorial. We demonstrate that vaccine-induced antibodies are able to inhibit the binding of infected erythrocytes to placental tissue receptors. We would like to optimize the vaccine to achieve higher levels of antibodies that are long lasting after as few doses as possible, preferably just one dose given to adolescent girls. This may be possible by advancing the vaccine using a virus-like particles, whereto the PAMVAC antigen is conjugated. Virus-like particles stimulate the antibody producing B cells to act faster and produce higher levels of antibodies. This way we hope to reduce the number of doses needed and have a longer-lasting response, so that it will be feasible to vaccinate adolescent girls.
ID CON: Your study might be the first report of a clinical trial that tested a vaccine to generate an antibody response against the molecular determinants of malaria. How might the prevention of malaria change because of these findings? What is the next step for getting the vaccine approved for widespread use?
MN: By targeting the virulence-associated antigens such the PAMVAC antigen, called VAR2CSA, the hypothesis is to alleviate the clinical symptoms, not necessarily the infection as such. The drawback is that these antigens are highly variable, so it may be difficult to achieve coverage. Therefore, vaccines targeting different stages of the parasite may be needed to attain efficacy. So not until trials demonstrating efficacy, potentially in combination with other vaccines, such as the RTS,S vaccine, have been concluded will this change how malaria in pregnancy is currently prevented.
ID CON: What else should ID specialists and public health providers need to know about your study?
MN: We are currently seeking funding to initiate new clinical trials. However, there is an association between the placental receptor called chondroitin sulfate A—carbohydrate attached to proteoglycans—and fast-growing cells, such as syncytiotrophoblast cells in the placental tissue. The association is the that fast-growing cells such as cancer cells also express this chondroitin sulfate A. So the malaria antigen VAR2CSA can be used to target and potentially treat cancer. So, we may be able to use knowledge about the manufacture of the protein from this line of development.
Reference:
- Mordmüller B, Sulyok M, Egger-Adam D, et al. First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria. Clin Infect Dis. 2019;69(9):1509-1516. https://doi.org/10.1093/cid/ciy1140.