Placental Malaria Vaccine Seems Safe, Immunogenic in Non-Pregnant Women

By Marilynn Larkin

February 25, 2020

NEW YORK (Reuters Health) - The first-in-human evaluation of a VAR2CSA-derived placental malaria vaccine suggests the vaccine is safe and immunogenic in malaria-naive and Plasmodium falciparum-exposed non-pregnant women, laying the groundwork for further study, researchers say.

The vaccine candidate, PRIMVAC, is being developed by Novartis, sponsor of the study.

"Pregnant women and children are the most vulnerable to malaria, and we cannot make progress without having a specific placental malaria vaccine for protecting pregnant women and their newborns," Dr. Benoit Gamain of Institut National de la Transfusion Sanguine in Paris told Reuters Health by email.

The double-blind, placebo-controlled, dose escalation trial enrolled 18 malaria-naive women ages 18-35 in France and 50 similar women in Burkina Faso who were naturally exposed to P. falciparum and nulligravid.

Participants received PRIMVAC intramuscularly on days 9, 28 and 56 at doses of 20 mcg or 50 mcg in France and 50 mcg or 100 mcg in Burkina Faso. Recipients also were randomly assigned to PRIMVAC adjuvanted with either Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE).

As reported in The Lancet Infectious Diseases, no serious adverse event related to the vaccine occurred. Vaccine antibody titers increased with each dose and all vaccinated women seroconverted.

Antibody titers peaked with the 100 mcg dose and GLA-SE one week after the third vaccination (day 63).

GLA-SE tended to improve the vaccine's antibody response compared with Alhydrogel. One year after the last vaccination, 20 (71%) of 28 women who were vaccinated with PRIMVAC/Alhydrogel and 26 (93%) of 28 women vaccinated with PRIMVAC/GLA-SE still had anti-vaccine antibodies, although the antibody magnitude was considerably lower. Further, these antibodies reacted with native homologous VAR2CSA expressed by NF54-CSA-infected erythrocytes.

Cross-reactivity against heterologous VAR2CSA variants was limited and only observed in sera collected from women who received the 100 mcg dose. "An alternate schedule of immunization, antigen dose, and combinations with other VAR2CSA-based vaccines are envisaged to improve the cross-reactivity against heterologous VAR2CSA variants," the authors conclude.

Dr. Gamain said, "Follow-up of the Burkinabe women vaccinated with PRIMVAC is important to provide additional information on the long-term immunity and indications as to whether or not the vaccine could help these women in accelerating clinical protection against placental malaria," he said. "With successful completion of the follow-up study, it is expected that (the vaccine) could move to a phase II clinical trial for further immunological and safety assessments."

"The biggest challenge now is to convince funders that developing a specific placenta malaria vaccine is needed in the global effort to eradicate malaria," he added. "Obtaining funds to further develop and move the vaccine forward is a priority. Deployment of the vaccine is still a long way off, but industry and funders will have to cover costs of production and vaccinations."

Dr. Claudia Daubenberger of the Swiss Tropical and Public Health Institute in Basel, author of an accompanying editorial, commented in an email to Reuters Health, "In clinical studies including pregnant women, it may be difficult to dissociate risks inherent in pregnancy from those associated with a vaccine tested."

"Knowledge of background rates of adverse pregnancy outcomes is essential when assessing adverse events after vaccination to understand potential causality," she said. "Surprisingly, information on background rates of adverse pregnancy outcomes is limited to non-existent in many parts of the world."

Other critical questions, she said, include how to demonstrate vaccine safety and protective efficacy in the field, including the best time to vaccinate during pregnancy; whether the vaccine will require a booster and what the optimal timing would be; which trimester women should be enrolled in a trial; whether the vaccine will be tested in nulligravida, secundigravida, or multigravida women; and whether it is possible to develop a universal vaccine that protects >75% of pregnant women against all circulating malaria strains globally.

Like Dr. Gamain, she noted, "Of great relevance might be now to ask who is willing to finance, drive and coordinate the development and licensure of a malaria vaccine designed for pregnant women?"

Dr. Jennifer Makin, Assistant Professor, UPMC Magee-Womens Hospital in Pittsburgh, told Reuters Health by email, "My largest concern is that there are many variants of malaria, so many that...you cannot develop full immunity to malaria. Many adults contract malaria repeatedly throughout their life and compare it to the flu or the cold. If the final vaccine product cannot manage to create more cross-reacting antibodies to other variants, I fear it may not be clinically effective in at preventing placental malaria in real life settings."

SOURCE: http://bit.ly/37VvNJt and http://bit.ly/2w3GM6c The Lancet Infectious Diseases, online February 4, 2020.

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