The long road to a malaria vaccine that’s safe during pregnancy

A malaria vaccine candidate has shown promising results in protecting women of childbearing age from infection — a protection that can extend during pregnancy. In a Phase 2 trial conducted in Mali, women who were planning to get pregnant were given doses of the first-generation PfSPZ vaccine by U.S.-based biotechnology company Sanaria. The trial showed the vaccine could protect the women against malaria infection for at least two years — through two malaria transmission seasons — without receiving a booster dose. Protection was also observed among those who became pregnant after vaccination, and the vaccine was well-tolerated and safe among mothers and their newborns. The results pave the way for the vaccine to be trialed in pregnant women, a population that suffers greatly when infected with malaria. In Africa, where the majority of cases are caused by the parasite Plasmodium falciparum, malaria is known to cause an estimated 50,000 maternal deaths during pregnancy and 200,000 stillbirths annually. But no vaccine has been tested or approved for pregnant people, who are often excluded from clinical trials due to safety concerns. The two WHO-approved malaria vaccines, R21 and RTS,S, are currently only recommended for children under 5 years old, although there’s a study planned to also assess the safety and efficacy of R21 in women of childbearing age in Mali. The results Sanaria’s first-generation PfSPZ vaccine uses radiation to weaken the malaria parasite, so when it enters the liver it cannot replicate and cause disease. Previous trials have shown it protected adults against malaria infection during a transmission season in Mali, but the Phase 2 trial has shown it can also provide protection for vaccinated women when they become pregnant. Women were on birth control before receiving the first dose of the vaccine, and until four weeks after the third and last dose, to prevent pregnancy while the vaccine course was in progress. In the trial, they were given either a lower dose of the vaccine, a higher dose of the vaccine, or saline as a placebo. For women who received lower doses of the vaccine, the efficacy of protection against infection was 41% in the first year and 61% in the second year. For those who received higher doses of the vaccine, efficacy was 54% in the first year, then dropped to 45% in the second year. The vaccine showed 49% to 57% efficacy among women who became pregnant after vaccination during the two-year trial period. Protection was as high as 86% during the first year among those who received higher doses of the vaccine and became pregnant within six months after vaccination. According to Sanaria, this is the first time a malaria vaccine has shown protection for this population. “WHO’s target [is] 90% protection against infection for an elimination vaccine. But think about what it would be for pregnant women if we just prevented 50% of the cases of malaria, which could cut down on stillbirths by at least 100,000 and maternal deaths by 25,000,” Dr. Stephen Hoffman, CEO of Sanaria, told Devex. According to an expert commentary in the Lancet Infectious Diseases journal, “Unlike other malaria vaccines, the PfSPZ Vaccine provided more durable protection with sustained immune responses during years 1 and 2 in the absence of boosting.” Before vaccination, all the women were given artemether-lumefantrine as a preemptive antimalarial treatment, which appears to have played an important part in the trial results. This suggests that “vaccine efficacy was improved by — and might be contingent on — previous clearance of acute infection,” according to an expert commentary. “I think it’s important to explore whether presumptive antimalarial treatment prior to first vaccination with other malaria vaccines can enhance immune responses,” Stephanie Yanow, professor in global health at the University of Alberta in Canada and co-author of the Lancet commentary, wrote in response to Devex. Given that “malaria is a tough nut to crack,” Hoffman said combining antimalarial drugs and a vaccine is better than either one alone. “What we found in a number of studies is unless we get rid of the parasites before we immunize, that the vaccine doesn’t work significantly,” he said. Future studies The vaccine provides “hope” for women who want to have a safe pregnancy in countries where malaria is a danger, according to Dr. Halimatou Diawara from the Malaria Research and Training Center in Mali, who led the trials for the vaccine there. She sees the vaccine as an additional weapon in the fight against malaria. The next step is to test the vaccine in pregnant women — and Diawara said they have already received regulatory approval to move ahead in Mali. She expects to start the trial in early 2025. Their plan is to first trial the vaccine on women in their second and third trimesters of pregnancy, and then, if all goes well, to test it on women during their first trimester of pregnancy. It’s uncommon to test vaccines on pregnant women, but Diawara believes it will be welcomed, especially in a place like Mali, where malaria remains a huge problem. The trial on pregnant women will continue to use Sanaria’s first generation vaccine. But outside of that, Sanaria plans to focus future trials on their third-generation malaria vaccine, PfSPZ-LARC2, which uses gene editing to weaken the malaria parasite. This allows the parasites to fully develop in the liver like normal parasites, but then disintegrate, rendering them noninfectious yet capable of inducing a strong protective immune response. The company had originally planned to go on a Phase 3 trial for their first-generation vaccine in Equatorial Guinea, with funding from the government itself and several U.S. energy companies, led by Marathon Oil. However, much of that funding was redirected to support the country’s response to COVID-19. At the same time, Sanaria was also finalizing the development of PfSPZ-LARC2, which Hoffman said “should be significantly more protective” than the company’s first-generation vaccine. Taking into account costs, the company determined it would be more cost-effective to focus on its third-generation vaccine, which Hoffman said would be five times cheaper to produce. They plan to start trials for PfSPZ-LARC2 in Germany, the United States, and Burkina Faso in the next six to nine months. “We think we can go extremely fast now … from phase one to phase two to phase three, because of all the foundation that’s been laid for the first two-generation vaccines,” he said. The company has several goals for its vaccine, but its initial priorities are to have a vaccine for travelers, women of childbearing age, and then children in Africa. It hopes to do this by getting a licensed malaria vaccine first in places like Europe and the U.S., and use the money from that to support the distribution of the vaccine in Africa and other developing countries. Fundraising will be crucial, given that it costs billions to develop a jab. “We have this small company that’s struggling every day just to stay alive to get the money to do this stuff,” Hoffman said, “so we have to be very careful about not overstretching.”