Pentavalent Vaccine Candidate for Meningitis Makes Its Case

In a randomized trial conducted in the African meningitis belt, an investigational pentavalent meningococcal vaccine proved safe and with noninferior immunogenicity to a licensed quadrivalent product, likely paving the way for a more affordable multivalent option.

The phase III study included individuals ages 2 to 29 years in Mali and Gambia, the target demographic in outbreak-response campaigns, and the pentavalent vaccine (NmCV-5) elicited similar seroresponse rates across shared serogroups along with favorable geometric mean titer (GMT) ratios versus the licensed vaccine, MenACWY-D (Menactra), according to Ed Clarke, MBChB, of the London School of Hygiene and Tropical Medicine in Banjul, Gambia, and colleagues.

On the basis of both seroresponse and GMT, noninferiority was demonstrated in all three age subgroups — 2 to 10 years, 11 to 17 years, and 18 to 29 years. The trial’s findings are expected to support the licensure and prequalification of NmCV-5 by the World Health Organization (WHO) as the first vaccine to target serogroup X, the researchers detailed in the New England Journal of Medicine.

For seroresponse measured at 28 days, the overall difference with NmCV-5 versus MenACWY-D, respectively, ranged from 1.2 percentage points (96% CI -0.3 to 3.1) for serogroup W to 20.5 percentage points (96% CI 15.4-25.6) for serogroup A, and the pentavalent vaccine also elicited a strong immune response for serogroup X:

• Serogroup A: 70.5% vs 50.0%
• Serogroup C: 97.9% vs 95.5%
• Serogroup W: 98.5% vs 97.4%
• Serogroup Y: 97.0% vs 92.0%
• Serogroup X: 97.2% vs 9.5%

GMT ratios favored the NmCV-5 vaccine across all serogroups of Neisseria meningitidis, the predominant cause of meningitis epidemics, ranging from 1.7 (95% CI 1.5-1.9) for serogroup A to 2.8 (95% CI 2.3-3.5) for serogroup C, with serogroup X responses also hitting prespecified criteria for noninferiority for both measures.

“On the basis of these trial data, NmCV-5 may emerge as a tool to support meningococcal disease control, particularly across the meningitis belt of sub-Saharan Africa, and thus may contribute to epidemic elimination and the other goals of the global road map for the Defeating Meningitis by 2030 program,” concluded Clarke and colleagues.

An estimated 2.5 million cases of meningitis were reported worldwide in 2019, resulting in more than 236,000 deaths and long-term neurologic disabilities or other complications for many who survive invasive disease. The highest burden is seen in the African meningitis belt — a stretch of sub-Saharan Africa spanning from Gambia and Senegal to Ethiopia.

While MenACWY-D and three other quadrivalent meningococcal conjugate vaccines targeting serogroups A, C, W, and Y have been licensed and prequalified by the WHO, supply and cost-constraints have limited their use, Clarke and fellow researchers explained.

“The technology that is used in the production of the NmCV-5 vaccine is based on cost-effective methods for carrier protein production, polysaccharide fermentation and purification, and chemical conjugation,” they noted. “Thus, the vaccine is expected to be made available at a cost lower than that of the existing quadrivalent vaccines.”

Of the six serogroups of meningococcus that can cause invasive disease (A, B, C, W, X, and Y), serogroup A had historically been the leading cause of disease in the meningitis belt, until mass vaccinations with MenAfriVac — led by PATH, the WHO, and others — virtually eliminated cases caused by this serogroup, noted David Stephens, MD, of Emory University in Atlanta.

“A powerful feature that contributes to the remarkable effectiveness of the MenAfriVac vaccine and other bacterial meningitis conjugate vaccines introduced in large-scale campaigns is the reduction of human-to-human respiratory transmission of encapsulated N. meningitidis and the induction of herd protection among unvaccinated persons,” he wrote in an accompanying editorial. “The effects on transmission can persist for decades.”

But despite this, epidemic outbreaks due to serogroups C, W, and more recently X still continue and NmCV-5 vaccine will likely play a role in the Defeating Meningitis by 2030 program, he said. The global road map aims to reduce meningitis epidemics and cut the rate of vaccine-preventable disease by 50% and mortality by 70%.

“One of the pillars of this effort is the development of new, affordable vaccines such as NmCV-5,” wrote Stephens. “Although challenges remain, we are a step closer to worldwide control of meningococcal disease and the burden of meningitis with these efforts.”

From August 2019 to June 2021, a total of 1,800 African participants at two centers in Gambia and Mali were randomly given either the pentavalent vaccine or quadrivalent vaccine in a 2:1 ratio, with vaccine responses measured after 28 days. Participants had a mean age of 13 years, 50.7% were female, and 43.4% were of the Mandinka-Malinke ethnic group.

For solicited adverse events (AEs), injection-site reactions were more common in the NmCV-5 group (26.0% vs 19.2% in the MenACWY-D group, P=0.001), with pain the most common reaction. Systemic solicited AEs were similar between the two vaccine groups (11.1% and 9.2%) and all were mild or moderate in severity.

Rates of mild or moderate unsolicited AEs were similar, at 15.8% after vaccination with NmCV-5 versus 16.5% with MenACWY-D. Most involved upper respiratory tract infections (4.6%), malaria (1.3%), or pharyngitis (0.8%), though none were considered related to vaccine. Three serious AEs were reported in each vaccine group, but again none were ultimately deemed related to vaccination.

Study limitations included the high baseline GMTs for serogroup A due to prior vaccination campaigns, and that vaccine efficacy wasn’t assessed, though the researchers noted that product licensure based on immunogenicity data is a “well-established” approach.

“Generation of effectiveness data regarding the NmCV-5 vaccine, particularly against serogroup X disease, will be important,” according to Clarke and team, who added that “data on the persistence of immune responses at 6 months and 12 months will be necessary, particularly considering the potential future routine use of NmCV-5 outside the epidemic response.”