Three novel pentavalent meningococcal vaccines

Invasive meningococcal disease (IMD) is an infectious disease with a mortality of 4–20% (pooled 8.3%) and long-term sequelae, which can result in devastating disability.^1,2 A recent French study about meningococcal meningitis in patients aged ≥18 years (median 30 years) included a follow-up at 12 months. More than 30% of the patients still had depressive symptoms or suffered of persistent headache. Another 15.5% had a hearing loss and the quality of life was significantly reduced. Also, 12.7% had not resumed their professional activity.³ In the even more often affected paediatric population, IMD additionally may result in mental retardation, cognitive impairment and behavioural disturbances; the case fatality rate may exceed 10%.¹

Globally, more than 90% of IMD is associated with six serogroups A, B, C, W, X and Y.¹ The distribution of serogroups varies geographically, temporally and with age groups.¹ Recently, Neisseria meningitidis B (NmB) predominated in outbreaks in the USA and causes some 60% of IMD in the developed world, but NmW and NmY are increasingly reported.¹ In the sub-Saharan meningitis belt, NmA has disappeared in most countries subsequent to campaigns with MenAfriVac®, a meningococcal conjugate group A vaccine.⁴ Overall, the incidence of IMD has decreased in that region, but severe outbreaks associated with NmC and NmW and circulation of NmX and NmW have been recorded besides other pathogens associated with meningitis⁴ (see also WHO Meningitis Weekly Bulletin, https://www.who.int/publications/m/item/meningitis-weekly-bulletin-1-to-7-may-2023).

In view of the severity of the disease and fluctuations in serogroups anywhere the news about a pentavalent MenABCWY vaccine is most welcome.⁵ This novel vaccine is comprising two licensed vaccines: the meningococcal serogroup B-factor H binding protein vaccine (MenB-FHbp, Trumenba®) and a MenACWY tetanus toxoid conjugate vaccine (MenACWY-TT, Nimenrix®). The vaccine injected intramuscularly at 0 and 6 months was highly immunogenic and well tolerated.⁵ The FDA has approved this first pentavalent vaccine (Penbraya™) on 20 October 2023 for use in individuals 10–25 years of age (https://www.fda.gov/media/173225/download?attachment).

A second pentavalent MenABCWY vaccine based on MenACWY-CRM (Menveo®) and 4CMenB (Bexsero®) has completed phase 3 in individuals aged 10–25 years with a 0, 6 months schedule. It was non-inferior as compared to its components and also for this vaccine there were no safety concerns (https://espidmeeting.org/wp-content/uploads/sites/19/2023/05/ESPID23-Abstracts-Book.pdf, Abstract O0085). The 4CMenB has been shown to offer some cross-protection against Neisseria gonorrhoeae as it is closely genetically related to N. meningitidis with 80–90% sequence homology. The vaccine effectiveness of 32–42% was modest, but nevertheless the Joint Committee on Vaccination and Immunization on 10 November 2023 has agreed that a targeted programme should be initiated using the 4CMenB vaccine for the prevention of gonorrhoea in those who are at greatest risk of infection (https://www.gov.uk/government/publications/meningococcal-b-vaccination-for-the-prevention-of-gonorrhoea-jcvi-advice-10-november/jcvi-advice-on-the-use-of-meningococcal-b-vaccination-for-the-prevention-of-gonorrhoea#:∼:text=The%20JCVI%20considered%20the%20evidence,at%20greatest%20risk%20of%20infection).

Recently, glycoconjugate vaccines against NmX have been developed and integrated in a third pentavalent vaccine.⁶ This novel MenACWXY vaccine elicited non-inferior immune responses to those elicited by the MenACWY-D vaccine and a good response to NmX. There were no safety concerns.⁶ The WHO Strategic Advisory Group of Experts on Immunization has endorsed it. SAGE recommended that all countries in the African meningitis belt introduce the novel pentavalent meningococcal conjugate vaccine targeting serogroups A, C, Y, W and X (Men5CV, also abbreviated NmCV-5) into their routine immunization programmes in a single-dose schedule at 9–18 months of age. In high-risk countries, and countries with high-risk districts, a catch-up campaign should also be conducted at the time of the introduction of Men5CV, targeting all individuals aged 1–19 years. … The implementation of the recommendation will be instrumental in eliminating meningitis epidemics in the meningitis belt as envisioned in the 2030 global WHO road map (https://cdn.who.int/media/docs/default-source/2021-dha-docs/highlights-3.pdf?sfvrsn=9237c77d_1&download=true).

To what extent are travellers at risk of IMD? IMD is rare in usual travellers not attending mass gatherings and not occurring significantly more often than while staying at home; but nowhere there is zero risk.⁷ Among 103 739 ill European travellers, 9 cases of meningococcal meningitis were reported among the ‘rare diagnoses’.⁸ Among 24 confirmed cases of meningitis in travellers, there was a single case of IMD in a student who returned from Germany.⁹ Additionally, anecdotal reports on IMD in tourists, business travellers, participants in mass-gatherings (sports event, funeral, jamboree, refugee camps) and in-flight transmission have been published.^7,10,11 Also, clusters of IMD among men who have sex with men (MSM) may have been associated with travel.¹² In the past, frequent outbreaks of IMD occurred after the Hajj, but mandatory vaccination with MenACWY eliminated pilgrimage associated outbreaks after 2001 despite suboptimal compliance.²

When would any of the novel pentavalent vaccines be indicated for travellers? In many countries, various monovalent or tetravalent MenACWY vaccines are already recommended mainly for children and adolescents and also for individuals with risk factors. To note, in the French patient cohort, 45.9% had at least one risk factor,³ such as immunodeficiency, asplenia or hyposplenia, autoimmune disorders, haemophilia, chronic respiratory disorders. A pre-travel consultation is the opportunity for the implementation or application of catch-up doses as per the respective national recommendations.

The Kingdom of Saudi Arabia annually publishes health requirements for visitors: ‘all individuals, aged 1 year or older, arriving for hajj or for work in hajj zones’ from any country must have received a ‘quadrivalent (ACWY) polysaccharide vaccine within the last 3 years’ or the respective ‘… conjugate vaccine within the last 5 years’. The same applies for those who travel to do the Umrah pilgrimage (https://www.moh.gov.sa/en/HealthAwareness/Pilgrims_Health/Documents/Health-Regulations-Umrah-EN.pdf). Some educational institutions in the United States and Canada similarly require that the students must have meningococcal vaccination and those attending from abroad must comply.

Besides such requirements or routine vaccination recommendations, various expert groups have issued recommendations for travellers. Primarily, this concerns residence or visits in sub-Saharan Africa mainly during the dry season (December to June). The intensity of contact with locals (e.g. visits to schools, visiting friends and relatives [VFR]), duration of stay, and host factors should be taken into account). For this destination, the single-dose MenACWXY vaccine to be produced in India would be most appropriate if marketed in the industrialized world and if it shows efficacy beyond small children and teenagers. Also, travellers to other countries where outbreaks of IMD are recognized should be recommended vaccine protection. As circulating strains vary, broad protection with pentavalent vaccines would be advantageous, but a 0, 6 months schedule is not practical in travellers. If a single dose offers at least short-term protection or if the schedule can be shortened to 0, 1 month—hopefully beyond the 10–25 years age group—novel pentavalent MenABCWY vaccines should at least be considered for travellers attending mass gatherings. The same should apply for potential high-risk exposure, such as it may occur in disaster relief workers, military missions, students attending crowded colleges and MSM. Whether or not health professionals should be immunized depends of the epidemiological situation, duration of exposure and detailed characteristics of the stay.

In summary, travel health professionals must identify at risk travellers for IMD considering their environmental exposure depending on the destination and travel characteristics and also individual host factors. The manufacturers of pentavalent meningococcal vaccines need to provide additional data with respect to their use in a broad range of age groups with a schedule that is suitable for travellers.

Funding

This perspective was not supported by any funding.

CRediT statement for author contributions

Robert Steffen (CRediT contribution not specified), Eric Caumes (Conceptualization [Equal], Data curation [Equal], Writing—original draft [Equal], Writing—review and editing [Equal]).

Conflict of interest: In the past 3 years, RS has obtained support for research, lectures or participation in advisory boards from Bavarian Nordic, GlaxoSmithKline, MSD/Merck, Pfizer, Sanofi, Takeda and Valneva. In the past 3 years, EC has received fees for lectures, or participation in advisory boards from Takeda and Valneva.

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