Development of MenFive®, an affordable pentavalent meningococcal conjugate vaccine (ACYWX) for Africa and beyond

ABSTRACT

Wide use of the groundbreaking vaccine MenAfriVac® has eliminated serogroup A meningococcal meningitis in the African meningitis belt and paved the way for elimination of all meningococcal disease outbreaks with the development, licensure, and introduction of an affordable multivalent conjugate vaccine that covers all disease-causing serogroups in the region. With supportive funding from the UK government’s Foreign, Commonwealth & Development Office, the global public health nonprofit PATH, and the Serum Institute of India Pvt. Ltd. extended their collaboration on MenAfriVac to develop, license, and World Health Organization prequalify MenFive®, an ACWYX meningococcal conjugate vaccine. The task of developing a low-priced, strongly immunogenic, pentavalent meningococcal conjugate vaccine required multiple collaborators and complex coordination, with numerous challenges and lessons learned. Importantly, MenFive has the potential to eliminate meningococcal disease outbreaks—not only in Africa (with recent deployment of outbreak response during the 2024 and 2025 meningitis seasons) but also in other regions of the world.

Introduction

Meningococcal meningitis, caused by Neisseria meningitidis, has long been an important public health problem in sub-Saharan Africa. Though it can occur anywhere in the world, it is most prevalent in Africa’s meningitis belt—26 countries stretching from Senegal to Ethiopia, where annual outbreaks and epidemics have led to tens of thousands of cases and thousands of deaths per year.¹ Historically, the largest and most common epidemics were caused by serogroup A meningococcus (MenA), but epidemics due to serogroups C, W, and X also occur—and for too long, affordable, effective vaccines for this region have been in short supply.²

Until 2010, reactive, emergency mass vaccination campaigns using polysaccharide vaccines were the primary response to these epidemics. But there were notable problems with this approach. Polysaccharide vaccines are ineffective in children younger than 2 years of age, and protection is short-lived. Moreover, it takes time to identify the causative agent and procure and administer the appropriate vaccines; as a result, vaccination campaigns were often conducted well after epidemics had swept through affected areas.

The particularly severe 1996/97 MenA epidemic, which sickened more than 200,000 and killed more than 20,000, spurred an international reassessment of control strategies and a call for new, Africa-specific meningococcal conjugate vaccines.³ In 2001, the Meningitis Vaccine Project, a collaboration between the global public health nonprofit PATH and the World Health Organization (WHO), with funding from the Gates Foundation, was founded to develop, test, license, and introduce an affordable MenA conjugate vaccine specifically for sub-Saharan Africa—MenAfriVac®.

Developed by the Serum Institute of India Pvt. Ltd. (SIIPL), MenAfriVac was introduced in December 2010 for mass vaccination campaigns. Public acceptance was excellent and post-campaign results were dramatically positive, with MenA outbreaks disappearing wherever the vaccine was used. Over the next decade, 24 meningitis belt countries introduced MenAfriVac and immunized more than 350 million people.^4,5 Following MenAfriVac introduction, an analysis of surveillance data in nine countries estimated the vaccine’s impact on serogroup A meningitis led to a 57% reduction in incidence levels of suspected meningitis, a 59% reduction in epidemic risk, and more than 99% reduction of serogroup A disease in fully vaccinated countries,⁶ with the last confirmed case in the meningitis belt occurring in 2017.⁵

MenAfriVac’s success focused attention on other meningococcal serogroups circulating in the meningitis belt. MenC, W, Y, and X epidemics never reached the magnitude of MenA epidemics, but they nevertheless remained a concern, with tens of thousands of cases each year resulting in thousands of deaths and many survivors with long-term, debilitating sequalae. For example, large MenC outbreaks occurred in Nigeria and Niger from 2014 to 2017 and MenW has been implicated in large epidemics for decades.⁷ Moreover, MenX—for which, at the time, there was no licensed vaccine—has demonstrated epidemic potential, with increasing cases reported in countries across the meningitis belt.⁸ For instance, in Ghana, cases of MenX have been on an upward trajectory since 2016, accounting for 81.8% (54 cases) of the total meningococcal meningitis cases in 2020, compared with only 1.1% (1 case) in 2016.⁹ A marked increase in the incidence of MenX cases was also noted in Niger in 2017 and 2018.¹⁰ Variants within clonal complex 181 have been responsible for most of the MenX disease in sub-Saharan Africa and have been circulating in the region since the 1970s⁸. Outside of Africa, MenX outbreaks have been relatively rare, but cases have been reported in industrialized countries, including in Europe and North America, since the 1980s, with an estimated global proportion of 0.7% causing invasive meningococcal disease.¹¹ The ratio of cases to carriers has been reported to be significantly lower for MenX compared to MenA, but dominant virulent clones of MenX are responsible for the majority of disease.¹²

Given the growing threat posed by non-A meningococcal disease, African public health experts pushed for the development of an affordable multivalent meningococcal conjugate vaccine (MMCV) that would protect against all disease-causing serogroups—including MenX.

In 2009, with funding from the UK government’s Foreign, Commonwealth & Development Office (FCDO), PATH and SIIPL came together to develop an affordable meningococcal ACYWX conjugate vaccine primarily for Africa. The resulting vaccine, MenFive®, builds on the legacy of MenAfriVac and has the potential to eliminate meningococcal meningitis outbreaks and epidemics in the meningitis belt. Prequalified by the WHO in July 2023, MenFive protects against the five predominant causes of meningococcal disease in the meningitis belt and is the first—and only—vaccine licensed to protect against MenX.

The MenFive partnership

MenFive (also known as NmCV-5 and Men5CV) development extended the meningococcal vaccine partnership between PATH and SIIPL. SIIPL was a critical partner for MenAfriVac in that it was willing to develop the vaccine at the price set by African health ministers (<US$0.50 per dose at launch). We added a new funding partner in FCDO and then rekindled valuable partnerships formed during MenAfriVac’s development (Table 1).

• The UK Health Security Agency’s (HSA’s) Vaccine Evaluation Unit (formerly Public Health England) conducted the immunological assessment for the Phase 1 and 2 clinical trials and the Phase 3 Expanded Program on Immunization (EPI) study.

• The UK National Institute for Biological Standards and Controls (NIBSC) conducted quality control testing of polysaccharides, conjugates, and final product batches manufactured for clinical trials (Table 2).

• WHO provided critical input on prequalification requirements and policy.

• The Center for Vaccine Development (CVD)-Mali and the Medical Research Council Unit The Gambia conducted clinical studies in Africa.

Table 1.

List of collaborators that contributed to the development of MenFive.

Collaborator	Role
4Clinics	Medical writing
Andrew Lees (FinaBiosolutions)	Scientific advisor and inventor of CPPT conjugation technology
Gates Foundation	Supplemental project funder and policy input
Center for Vaccine Development and Global Health (Maryland)	Clinical trial site and implementor (US)
Center for Vaccine Development-Mali	Clinical trial site and implementor (Africa)
DiagnoSearch Life Sciences Pvt. Ltd.	Contract research organization (India)
The Emmes Company, LLC	Clinical research organization (US)
Indian Trial Sites	Hamdard Institute of Medical Sciences and Research, Delhi Institute of Medical Sciences and SUM Hospital, Bhubaneshwar, Orissa Jahangir Clinical Development Centre Pvt. Ltd., Maharashtra KEM Hospital Research Center, Maharashtra Kempegowda Institute of Medical Sciences, Bangalore, Karnataka M S Ramaiah Medical College and Hospitals, Bangalore, Karnataka Mahatma Gandhi Institute of Medical Sciences, Sewagram, Maharashtra Post Graduate Institute of Medical Education and Research, Chandigarh Seth G S Medical College & KEM Hospital, Maharashtra Sri Ramachandra Institute of Higher Education and Research, Tamil Nadu TN Medical College & BYL Nair Hospital, Maharashtra
John Hennessey	Consultant
MCT	Contract research organization (Africa)
Medical Research Council Unit – The Gambia	Clinical trial site and implementor (Africa)
MenAfriNet	Epidemiology
Meningitis Research Foundation	Policy and advocacy
MPI/Charles River Laboratories	Preclinical toxicology studies
Neil Ravenscroft	Consultant
Nexelis (formerly NEOMED-LABS)	Clinical serology
Parexel International Pvt. Ltd.	Clinical research organization (African trials)
PATH	Project collaborator, subject matter expert, technical consultant; design and sponsor for Africa clinical trials; regulatory facilitation for World Health Organization prequalification
PPD Pvt Ltd.	Contract research organization (Indian trials)
Serum Institute of India Pvt. Ltd.	Product developer and manufacturer; India clinical trial design, sponsor, and conduct; regulatory facilitation for Indian export license and marketing authorization; design for Africa clinical trials; regulatory facilitation for World Health Organization prequalification
Simonetta Viviani	Consultant
UK government Foreign, Commonwealth and Development Office (formerly UK government Department for International Development)	Project funder
UK Health Security Agency (formerly Public Health England) Vaccines Evaluation Unit	Clinical serology and assay expertise and conduct
US National Institute of Allergy and Infectious Disease Infectious Diseases Clinical Research Consortium	Funding and conduct of Phase 3 trial in young children 9–15 months of age
UK National Institute for Biological Standards and Controls	Vaccine and manufacturing intermediate quality control assays
VisMederi	Testing laboratory for EPI serology (pediatric EPI study)
WHO	Project collaborator, epidemiology, prequalification guidance, policy and advocacy

Table 2.

List of technical and regulatory consultative meetings conducted during the development of MenFive.

Agency	Date	Topic of Discussion
Central Drugs Laboratory – The National Control Laboratory, India	March 2015	Submission of Phase 1 batches and CMC updates for Phase 1 batch testing and release
	January 2018	Updates on CMC and Phase 2 batches testing and release
	April 2019	Updates on CMC and submission of Phase 3 and Phase 2/3 lots for testing and release
Drugs Controller General of India	December 2013	Discussion of and agreement on clinical developmental pathway
Drugs Controller General of India – Subject Expert Committee	September 2019	Discussion on Phase 2/3 clinical trial application
International Coordinating Group on Vaccine Provision	September 2021, October 2022, July 2023	Annual meningitis meetings
National Institute for Biological Standards and Controls, UK	September 2016, June 2019	Testing of polysaccharide, conjugates, and final product batches manufactured for Phase 1, Phase 2, and Phase 2/3
Paul Ehrlich Institut, Germany	January 2015	Consultation on CMC and clinical development
	March 2020	Updates on CMC and Phase 3 clinical; possibility of European Union-submission for marketing authorization
SAGE working group on meningococcal vaccines and vaccination	October 2019	Update working group on MenFive development progress and plans for licensure and WHO prequalification
US Food and Drug Administration	September 2015	Pre-IND meeting
	May 2016	Phase 1 IND submission
WHO Strategic Advisory Group of Experts on Immunization (SAGE)	July 2022, September 2023	Annual meetings
World Health Organization	January 2014	Consultation on CMC and clinical development
	April 2017	Updates on CMC and Phase 2 clinical development
	October 2018	Updates on CMC and Phase 3 clinical development
	March 2020	Scientific advice meeting with WHO
	October 2020	Regulatory strategy alignment meeting with WHO/DCGI/SIIPL
	November 2021	Meeting requested and briefing slides submitted, however, no meeting conducted in light of the WHO workload for assessing EULs for COVID-19 vaccines

Additionally, the US National Institute of Allergy and Infectious Diseases’ Infectious Diseases Clinical Research Consortium provided funding for and conducted the ongoing Phase 3 study in 9–15-month-old Malian toddlers.

MenFive research and development

At least 12 Neisseria meningitidis serogroups have been categorized based on the structure of their capsular polysaccharide and the immunological response elicited.¹³ Of these serogroups, six (A, B, C, W, Y, and X) are the most common causes of invasive meningococcal disease worldwide.¹⁴

In the early 2000s, meningococcal vaccine development by the multinational vaccine companies focused on quadrivalent (A, C, W, Y) conjugates and MenB protein vaccines. However, considering the evolving epidemiology of the meningitis belt—particularly the rise in MenX cases—and to align with WHO’s November 2011 meningococcal vaccine position paper, we focused on a pentavalent (A, C, W, Y, X) conjugate vaccine that would target all epidemic-causing serogroups in the African meningitis belt.¹⁵

Polysaccharide structure, strain selection, and polysaccharide purification process

The MenA and MenX polysaccharide structures have phosphodiester linkages, while serogroup C, Y, and W polysaccharides are sialic acid-based polymers. MenX polysaccharide is a homopolymer of (alpha 1–4) N-acetylglucosamine 1-phosphate, while MenA polysaccharide is O-acetylated repeating units of (alpha 1–6) N-acetyl monoamine phosphate.

Strain selection and development of the polysaccharide purification process focused on optimizing the polysaccharide yield and, therefore, minimizing the cost of manufacturing. Serogroups A, C, Y, W, and X bacterial strains were sourced from the Center for Biologics Evaluation and Research, within the US Food and Drug Administration (FDA), and the US Centers for Disease Control and Prevention (CDC). We continued to use the MenAfriVac serogroup A strain for MenFive development. The earlier manufacturing process at a 1000 liter fermentation scale produced about 200 grams of purified polysaccharides, while the newly developed, more efficient manufacturing protocols produced similar quantities of A, C, Y, W, and X polysaccharides but at a 400 liter scale. A polysaccharide manufacturing process was developed to retain critical antigenic epitopes that subsequently resulted in better immune responses in preclinical¹⁶ and, subsequently, human studies. The purification processes were designed and optimized using selective surfactant precipitation and alcohol extraction to separate endotoxin, protein, and nucleic acid impurities from polysaccharides. The O-acetylation levels were retained by avoiding harsh alkali or enzyme treatment.¹⁷ We screened six MenY strains (one from the UK HSA and five from the CDC) to obtain purified polysaccharide with the desired characteristics. Similarly, we screened five MenX strains (from CBER) to select one capable of producing polysaccharide of required structural characteristics and high yields. Uniform growth patterns and ease of processing were decisive for strain selection at a research scale.

The O-acetylation levels of purified polysaccharides of serogroups A, C, Y, and W were within the acceptable levels recommended by WHO in their Technical Report Series (TRS) guidance documents.^18–20 Partially O-acetylated polysaccharides of serogroups A > 65%, C > 50%, Y > 30%, and W > 35% were used for conjugation. MenX polysaccharide is non-O-acetylated. For MenX, the reported fermentation medium did not promote the desired cell growth and yield; therefore, we optimized a medium that showed uniform growth kinetics and high polysaccharide yields. In early process development, we used deoxycholate to purify capsular polysaccharides; it was later replaced with sodium dodecyl sulfate. The polysaccharide purification protocols were largely based on surfactant precipitation and alcohol extraction.

Conjugation

MenA, C, W, and X polysaccharides were mechanically size-reduced, while MenY polysaccharide was size-reduced via chemical treatment. The size-reduced polysaccharides of serogroups A and X were derivatized by an adipic acid dihydrazide linker using cyanalation chemistry followed by carbodiimide chemistry for covalent linking to purified tetanus toxoids. The size-reduced polysaccharides of serogroups C, Y, and W were covalently linked to the adipic acid dihydrazide derivatized recombinant CRM₁₉₇. The conjugation technology used a novel cyanylating agent, 1-cyano-4 pyrrolidinopyridinium tetrafluoroborate (CPPT), licensed from Fina BioSolutions (Maryland, USA). This new conjugation technology enabled higher conjugation efficiencies, better preservation of key immunological epitopes, and eased the manufacturing process compared to the reductive amination chemistry used to manufacture MenAfriVac.¹⁶

Because the MenX conjugate contained a novel serogroup polysaccharide not used previously in a licensed vaccine, we carried out extensive studies to finalize the polysaccharide size for conjugation and determine the use of a linker, the conjugation strategy (derivatizing either polysaccharide or carrier protein), and the extent of derivatization. We studied the immunogenicity of the finalized conjugate construct first in mice and then in rabbits; the tetanus toxoid- (TT)-conjugated MenX polysaccharide in the size range of 75–150 kD (by SE-HPLC) was highly immunogenic and was able to generate strong bactericidal activity compared to native polysaccharide, suggesting a T-cell dependent immune response.¹⁶ Since MenX polysaccharide has structural similarity to MenA polysaccharide, we referenced the WHO TRS for MenA conjugate vaccines to define the critical quality attributes for MenX polysaccharide and conjugate bulk drug substance.¹⁸ We evaluated various combinations of conjugates manufactured with different carrier proteins—diphtheria toxoid (DT), TT, and recombinant CRM₁₉₇—in a series of preclinical animal studies. The final decision to use two carrier proteins (TT for MenA and X and rCRM₁₉₇ for MenC, W, and Y) was primarily based on preclinical immunogenicity data and a need to overcome potential TT-associated carrier-induced immune supression.^16,18,21,22 Both TT and CRM₁₉₇ have been used successfully in licensed multivalent meningococcal conjugate vaccines, providing an additional rationale. Moreover, the inclusion of the two carrier proteins created an opportunity to boost both TT and DT responses in vaccines, a result subsequently observed in the Phase 2 trial conducted in toddlers in Mali (unpublished data), though it is not a label indication for the vaccine. Finally, the development of technology to store individual purified conjugates at −20°C allowed us to quickly convert drug substances to drug product, an important consideration in the case of a disease outbreak that required rapid availability of the vaccine.

Formulation development

To develop a heat-stable vaccine, critical for long-term stability and the potential for the WHO controlled temperature chain (CTC) indication, we explored spray-drying and lyophilization technologies along with a series of excipients for stabilization. Analysis showed MenA polysaccharide was most susceptible to thermal degradation, followed by MenC. The lyophilized conjugates were stored at 40°C and free polysaccharide levels were analyzed as a stability indicator. We preferred freeze-drying given the ease of commercial manufacturing, and sucrose and sodium citrate were selected from a screen of stabilizers. WHO agreed to a five-dose-per-vial presentation without preservative, with a requirement that the doses be administered within 6 hours of reconstitution. Lyophilized MenFive was found to be stable when stored at 25°C and 40°C for 6 and 4 months, respectively, and the vaccine was recently approved by the Indian National Regulatory Authority for CTC storage at 40°C for up to 28 days. In addition, extensive nuclear magnetic resonance spectroscopic analysis helped us monitor polysaccharide integrity during different manufacturing stages.

At every stage of development, purified polysaccharide, bulk conjugates, and final lot samples were shipped to NIBSC for additional quality testing and characterization. The results obtained by SIIPL and NIBSC demonstrated that the critical quality attributes—namely, level of O-acetylation, the integrity of the conjugated saccharides, and the level of endotoxin—were comparable.²³

Pre-clinical toxicology studies

Several Good Laboratory Practices (GLP)-compliant toxicology studies were performed for 4-pyrrolidinopyridine, the by-product of the CPPT conjugation chemistry and MenFive, to establish a safety profile prior to clinical study. These GLP-compliant studies included single-dose oral acute, single-dose intramuscular, skin sensitization, bacterial reverse mutation, and an in vitro mammalian cell gene mutation test. Additionally, we conducted a GLP-compliant repeat-dose toxicity study of MenFive both with and without adjuvant in rabbits and demonstrated that both formulations were safe and well tolerated. Finally, we conducted a GLP-compliant developmental and reproductive toxicology study in rats that showed MenFive was well tolerated and immunogenic both with and without adjuvant and did not adversely affect female fertility, embryo-fetal, or pre- and post-natal survival, growth, or development. All toxicology studies were conducted in the US at either the former MPI Research or Charles River Laboratories.

MenFive clinical development

The MenFive clinical development strategy was designed so that the vaccine would first be assessed in a high-income country with stringent national regulatory authority to establish initial safety and immunogenicity, then would rapidly transition to the African meningitis belt (where the target population resided) for Phase 2 and 3 studies (Table 3). Importantly, conducting the clinical trials in Africa wouldn’t just expedite vaccine development but would also help strengthen the skills and capacity of the sites for further capacity building—a critical issue for Africa that was highlighted during the COVID-19 pandemic.²⁴ In addition, SIIPL would pursue a Phase 2/3 trial to achieve marketing authorization in India while demonstrating lot-to-lot consistency for three manufactured lots.

Table 3.

Clinical trials conducted with MenFive.

Phase	Study Site(s)	Population	Number of subjects (NmCV-5/comparator)	Primary Objective	Status	Summary
1	US	18–45 years	20/20/20	Safety	Complete26	Demonstrated initial NmCV-5 safety and immunogenicity in adults.
2	Mali	12–16 months	150/150/75	Safety	Complete27	Demonstrated safety and immunogenicity in toddlers. Demonstrated boosting of DT and TT immune responses.
3	Mali and The Gambia	2–29 years	1200/600	Non-inferiority compared to licensed Men ACWY-D vaccine.	Complete28	Immunological non-inferiority demonstrated. Immunological persistence demonstrated through 12 months.
2/3	India	18–85 years	1230/410	Non-inferiority compared to licensed Men ACWY-D vaccine and lot-to-lot consistency	Complete29	Non-inferiority and lot-to-lot consistency demonstrated.
3	Mali	9–15 months	800/400	Non-inferiority compared to licensed ACWY-T vaccine and EPI non-interference	Ongoing (partial results available)30	Non-inferiority and EPI compatibility demonstrated.

Both the US and Europe were considered for the MenFive Phase 1 clinical trial, but it was ultimately conducted in the US—though the FDA indicated further development in the US would require establishing human complement serum bactericidal antibody (SBA) assays specific to each serogroup rather than using the rabbit complement SBA (rSBA) assays as we intended. WHO, on the other hand, indicated that rSBA was appropriate given the goal of demonstrating immunological non-inferiority to a licensed quadrivalent vaccine. The UK HSA laboratories had validated rSBA assays established for Men ACYW and were beginning work to validate a MenX rSBA; that, coupled with our past working relationship, made UK HSA a good choice for this work.²⁵

We selected CVD at the University of Maryland School of Medicine in Baltimore as the Phase 1 trial site to facilitate a smooth transition to a Phase 2 trial in Africa at the affiliated CVD-Mali. In the Phase 1 trial, 60 healthy adults 18–45 years of age received a single administration of MenFive alone (5 µg for each polysaccharide), MenFive adjuvanted with aluminum phosphate, or the licensed comparator vaccine Menactra® (ACWY-D). Menactra was selected as the comparator vaccine because it was the first quadrivalent conjugate vaccine to be licensed in the US (in 2005) and therefore was the most widely used vaccine with the most extensive effectiveness data as a result. Moreover, Menactra was WHO prequalified (in 2014) and allowed a seamless transition to subsequent clinical studies in Africa where a comparator vaccine was required to support licensure. Finally, the use of Menactra as the comparator vaccine was discussed with and agreed to by WHO. The dose selected for MenFive (5 µg of each polysaccharide) was based on preclinical studies with different formulations, the experience with MenAfriVac, and the fact that the licensed MenACWY vaccines all contained 4–10 µg of each polysaccharide per dose. In the Phase 1 trial, both the adjuvanted and nonadjuvanted MenFive formulations were well tolerated and neither produced concerning adverse effects. The resulting rSBA immune responses were predicted to confer protection against all five serogroups, and there was no discernable difference between the adjuvanted and non-adjuvanted formulations.²⁶

The Phase 2 trial was designed to further assess safety in 12–16-month-old Malian toddlers and definitively assess the need for the adjuvant. Given the recommended MenACWY-D schedule in 12-month-olds, we administered two MenFive doses three months apart and monitored immune responses pre- and post- each administration. Again, no safety concerns were identified. Importantly, a single dose of MenFive elicited immune responses similar to or higher than those observed with two doses of Menactra.²⁷ Adjuvanted MenFive provided no discernible benefit over the non-adjuvanted formulation, so the latter was selected for the subsequent Phase 3 trials.

Following discussions with the Drugs Controller General of India and WHO, we decided to pursue parallel Phase 3 programs in India and Africa. At the time, there was no WHO TRS for MMCVs, so we consulted WHO guidance for MenA and multivalent pneumococcal conjugate vaccines for proposed immunological non-inferiority criteria for the novel MenX component.

The Phase 3 trial in Africa was conducted in 1,800 participants 2–29 years of age in Mali and The Gambia.²⁸ Participants received a single intramuscular dose of either MenFive or Menactra. MenFive immune responses were non-inferior to those of Menactra for the four serogroups in common, as measured by either seroresponse rate or geometric mean antibody titers. The MenX component also met pre-specified non-inferiority criteria, whereby the MenX response was compared to the serogroup with the lowest response from the comparator vaccine—a comparison based on WHO guidance for novel pneumococcal serotypes. In addition, MenFive rSBA responses at 6- and 12-months post-immunization persisted well above baseline and at levels similar to the peak Menactra response seen at 28 days [manuscript in preparation]. Finally, the adverse event incidence was similar for both vaccines.

The Phase 2/3 trial in India was conducted in 1,640 adults 18–85 years of age and included lot-to-lot consistency for three manufactured lots of MenFive.²⁹ Each lot was immunologically consistent, as measured by rSBA response, for all five serogroups. Furthermore, MenFive demonstrated immunological non-inferiority to Menactra for all four serogroups in common, met the pre-specified non-inferiority criteria for MenX, and was safe and well tolerated.

Given the large number of participants in the Phase 3 trials and associated required rSBA testing, we partnered with Nexelis in Laval, Canada, to set up and validate a high throughput assay protocol specific to each serogroup to run clinical trial samples. The set up, validation, and control faced significant challenges that were overcome with substantial input and collaboration from PATH, SIIPL, UK HSA, and Nexelis. For example, because the assays established at Nexelis were essentially “owned” by PATH and SIIPL, we had to establish our own cell banks, positive controls, protocols, and validation, which required considerably more input and oversight than our previous work with UK HSA, which had already established its own validated assays that were used for its own research but also made available to collaborators.

The Phase 2 trial in Mali and the Phase 3 trials in Africa and India were designed to achieve WHO prequalification for a broad age group between 1 and 85 years, which would enable use in one-time preventive mass immunization campaigns in the African meningitis belt (and for travelers to endemic countries, including Hajj and Umrah pilgrims). However, to protect the new birth cohorts in the meningitis belt and to maintain population immunity, the vaccine needed to be part of the routine Expanded Programme on Immunization (EPI) schedules in infants/toddlers.

Therefore, one additional Phase 3 trial was required to allow routine use of MenFive in meningitis belt countries, though initiation was delayed due to lack of available donor funds. This trial was critical to the meningococcal outbreak elimination goal as WHO wanted the vaccine to be introduced for preventative campaigns and routine immunization simultaneously (see below). Eventually, funding from the US National Institutes of Health to a consortium comprised of the Infectious Disease Clinical Research Consortium, FHI 360, and the Statistical Center for HIV/AIDS Research and Prevention, together with supplemental funding from FCDO and SIIPL to PATH, was secured. The trial was designed to assess immunological non-inferiority of MenFive versus a comparator vaccine, when co-administered with EPI vaccines in children 9 and 15 months of age.³⁰ Nimenrix® (ACWY-TT) was selected as the comparator because it is administered as a single dose for this age range. Analysis demonstrated immunological non-inferiority for all five serogroups in both 9-month-old and 15-month-old children. Non-inferiority was demonstrated for co-administered measles/rubella and yellow fever vaccines, except for rubella responses at 9 months of age, and WHO confirmed that co-administration was acceptable for all three antigens. Local and systemic adverse events were generally mild and occurred at similar rates for both vaccines. Immune persistence assessments for 6 months and 2 years following immunization were ongoing at the time of writing.

Regulatory and policy

SIIPL, PATH, WHO, and other technical and regulatory authorities had ongoing discussions to facilitate an efficient licensure and WHO prequalification pathway for MenFive (Table 2). Given supply concerns related to polysaccharide vaccines stockpiled for emergency use and the potential for MenX outbreaks, WHO agreed the prequalification dossier could be submitted in parallel with the Indian export permit application. MenFive received full marketing authorization in India in September 2022 for 18–85-year-old individuals and WHO prequalification in July 2023 for 1–85-year-old individuals (with a subsequent amendment in March 2024 to lower the approved age to 9 months).

The MenAfriVac introduction strategy relied on initial mass vaccination campaigns in 1–29-year-old individuals, followed by routine immunization of 9–18-month-old children. This strategy protected vaccinated individuals while reducing MenA transmission via reduction of carriage and subsequent herd protection—and it was remarkably successful. A similar introduction strategy, but incorporating important lessons learned, was imagined for MenFive. For example, WHO and Gavi, the Vaccine Alliance envisioned that, in high-risk countries, MenFive would be introduced into routine immunization programs in parallel with mass vaccination campaigns, whereas for MenAfriVac there was a considerable lag between the initial campaigns and routine introduction that required subsequent catch-up campaigns to fill in the gap. Policymakers also considered using a narrower age range for the MenFive campaigns (e.g. 5–14 years versus 1–29 years) and uniform versus risk-based strategies in order to improve efficiency of the vaccine rollout and maximize cost-effectiveness.³¹

In May 2019, WHO established the Strategic Advisory Group of Experts on Immunization (SAGE) Working Group on meningococcal vaccines and tasked them with preparing a review of evidence and advising WHO on the use of meningococcal vaccines to mitigate the public health impact of the disease.³² The working group met regularly over the ensuing four years to review epidemiological data, use of meningococcal vaccines, MenFive safety and immunogenicity, and modeling studies on the impact of different vaccination strategies, ultimately presenting this data to SAGE together with draft recommendations. PATH also supported SIIPL’s interactions with global policymakers to help reduce bottlenecks and accelerate policy recommendations. In September 2023, SAGE recommended that all meningitis belt countries introduce MenFive into routine immunization programs in a single-dose schedule at 9–18 months of age and that high-risk countries and countries with high-risk districts conduct a catch-up campaign in individuals aged 1–19 or 2–19 years, depending on the age group covered by the routine immunization program. WHO subsequently published an updated position paper on the use of MMCVs in African meningitis belt countries in January 2024.³³

The licensure of MenFive and SAGE’s recommendation for its use in all meningitis belt countries means the goal of eliminating meningitis outbreaks in the region is now within reach. According to the SAGE recommendations, six meningitis belt countries (Niger, Nigeria, Ghana, Mali, Burkina Faso, and Chad) conducted risk assessments between August 2024 and January 2025 using three quantitative indicators of magnitude: disease burden, disease intensity, and frequency of epidemics. Based on these assessments, strategies for introducing MenFive have been proposed for 2025–2027 that combine mass vaccination campaigns with a progressive switch from MenAfriVac to MenFive in routine immunization programs.

More broadly, MenFive development aligns with a WHO-led initiative to defeat meningitis by 2030.³⁴ A road map outlining a global vision and strategic goals was adopted by the World Health Assembly in November 2020 and launched in September 2021. It cites the development of and enhanced access to affordable MMCVs as key in controlling meningitis and the introduction and uptake of MMCVs as a landmark achievement.

Key takeaways and lessons learned

MenFive development provides important lessons for accelerating vaccine development in low- and middle-income countries, including:

• Fostering trusted collaborations and maintaining partner continuity: MenFive development benefited from the relationships formed during MenAfriVac’s development. Because many collaborators had worked together previously, they were confident in each other’s capabilities and could easily apply previous learnings to MenFive. This helped expedite processes from conception to WHO prequalification and aligned the clinical program with regulatory authority expectations from the get-go. Collaborators were also aligned in their missions to advance vaccine access globally and promote health equity, which provided a guiding star for use-case and business decisions—ultimately resulting in a vaccine that aligns with Gavi expectations and is affordable for meningitis belt countries.

• Carefully considering manufacturing efficiency to keep vaccine price low: Because collaborators were committed to a low price-point for MenFive (no more than $3/dose per Gavi cost-effectiveness assumptions)—and because conjugate vaccines are costly and complex to make—it was essential to optimize manufacturing in a way that would keep costs low and yield a more affordable product. By ensuring efficient yields for polysaccharide manufacturing and conjugation, and by pursuing a multidose presentation from the beginning, collaborators were able to mitigate some of the more significant costs and produce an effective vaccine that makes economic sense for all stakeholders.

• Demonstrating flexibility and responsiveness as issues arose: The MenFive development program faced numerous unexpected challenges, from a cybersecurity attack that funneled time and attention away from vaccine development to managing high volumes of samples and complex immunological assays in Phase 3 trials to funding shortfalls that delayed clinical activities. However, in all cases, collaborators quickly adjusted plans to ensure the development program moved forward. In particular, the strength and flexibility of the PATH/SIIPL partnership allowed us to maintain continuity in clinical study contracting, planning, and oversight. This reassured partners and stakeholders and reinforced commitments to MenFive and meningococcal meningitis prevention.

• Capacity building for clinical trials in Africa: From the MenFive project inception, PATH and SIIPL were committed to conducting key clinical trials in Africa since the prime target for the vaccine was populations in African meningitis belt countries. This proved to be prescient given the impact of the COVID-19 pandemic and subsequent recognition that clinical trial capacity building is essential to augment the continent’s pandemic prevention, preparedness, and response efforts.²⁴

• Investing in a local presence: Travel was suspended and international borders closed when the COVID-19 pandemic struck, which could have halted clinical activities. However, because we invested in partners with locally trained staff, they could continue visiting study sites and carrying out many clinical operations. It demonstrated the importance of engaging local experts for maintaining operational continuity and alleviating logistical risks when working across borders.

• Aligning policy with other stakeholders: Establishing pathways to quickly move MenFive to market was a foundation of the development program. Stakeholders wanted to avoid MenAfriVac’s introduction strategy—first in mass vaccination campaigns, then years later in routine use that required catchup campaigns—so MenFive’s development and regulatory strategy were early-on crafted to support simultaneous introduction. Aligning policy and strategy was also critical for demand forecasting, which had major implications for SIIPL’s business case, and for determining what would be considered “cost effective” in the meningitis belt. For instance, MenFive had to meet the no-more-than US$3 per dose price assumed by Gavi’s Vaccine Investment Strategy (a process for prioritizing new and under-used vaccines and determining which they will support) to be appropriate for use. These broader policy alignments set the MenFive development program up for success and ensured the vaccine would be positioned to save as many lives as possible.

Looking to the future

The hard work of developing an effective vaccine and pursuing licensure and WHO prequalification is done, but continued efforts are underway to make MenFive broadly available. An extension study of the African Phase 3 trial has shown immune responses to all vaccine serotypes remain well above pre-immunization levels 12 months after vaccination, which augers well for long-term protection. But further analysis of the persistence of immunity beyond 12 months—ideally, 5 years or more—will be essential for determining the potential need and timing for a booster dose. We also plan to conduct a Phase 3 study of MenFive in Indian children between 9 months and 17 years of age to demonstrate immunological non-inferiority to Menactra, the results of which will allow the original Indian marketing authorization to be expanded to pediatric age groups.

Continued study will ensure as many people as possible will have access to MenFive—key to accessing the vaccine’s potential to eliminate meningococcal outbreaks and epidemics from the meningitis belt. The first steps toward that goal were taken in March 2024, when MenFive was used for the first time in Nigeria to combat a MenC outbreak in a campaign that targeted about 1 million children and adolescents; shortly after, Niger procured more than 800,000 doses of MenFive to tackle outbreaks of MenC and MenW.^35,36 The biggest impact, however, will come when MenFive is used as a preventative tool. Monitoring MenFive’s impact on disease caused by the serogroups included in the vaccine will be essential and, as part of the rollout, it will be critical to determine whether MenFive’s impact on carriage of non-A serogroups is similar to that of MenAfriVac’s on MenA carriage, which was critical for establishing herd protection and the rapid elimination of MenA disease following the MenAfriVac mass vaccination campaigns.⁶ Moreover, given MenFive’s potential to reduce the carriage of all the major disease-causing meningococcal serogroups in the meningitis belt, it will be important to monitor for replacement carriage and diseases—such as that caused by serogroup B meningococcus, which historically has rarely been detected in the meningitis belt. The potential for replacement disease was a concern with the rollout of MenAfriVac and, although an increase in the incidence rate of non-A serogroups was observed in MenAfriVac-vaccinated populations, it is not clear whether this was due to an artifact from improved surveillance, natural variations in meningococcal infections, or serotype replacement.⁶

MenFive has potential beyond Africa, too, and could one day be used globally for travelers including Hajj and Umrah, people living in areas where MenX is a problem, or in middle- and high-income countries where meningococcal vaccines are in limited use due to cost-effectiveness barriers.

MenFive licensure and WHO prequalification are remarkable achievements that are poised to change the course of meningococcal disease in Africa and beyond. The availability of an MMCV like MenFive will play a key role in the Defeating Meningitis by 2030 “visionary goals” of eliminating bacterial meningitis epidemics and reducing cases of vaccine preventable by 50% and deaths by 70%.³⁴ Swift and successful development would not have been possible without the committed partners and stakeholders that provided essential input, funding, guidance, and expertise.

Biography

Mark R. Alderson is the Chief Scientific Officer at Maxvax Biotechnology LLC, Seattle, WA, USA. Prior to this, he was the Bacterial Vaccine Initiative Leader with PATH’s Center for Vaccine Innovation and Access, playing a lead role in the development of vaccines against pneumococcus, meningococcus, and Group B Streptococcus. Dr. Alderson led the PATH team that worked with the Serum Institute of India to develop, license, and WHO prequalify the 10-valent pneumococcal conjugate vaccine, PNEUMOSIL®, and the 5-valent meningococcal conjugate vaccine, MenFive®. Prior to joining PATH, Dr. Alderson was Director of Immunology at GlaxoSmithKline Biologicals, Seattle, WA, USA where he led preclinical work on synthetic adjuvants for a variety of vaccine targets. Prior to GSK, he was Senior Director of Immunology at Corixa Corporation, where he was responsible for the preclinical discovery and evaluation of adjuvants and vaccines for tuberculosis, Chlamydia, and Herpes simplex virus. He served as an Affiliate Associate Professor, Department of Pathobiology, at the University of Washington from 2002 to 2006. Dr. Alderson earned his PhD at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia and his MBA at Seattle University, USA.

Funding Statement

This work is based on product development funded by the UK government’s Foreign, Commonwealth & Development Office.

Disclosure statement

Drs. Kulkarni, Pisal, LaForce, and Dhere are or were formerly employed by SIIPL, the manufacturer of MenFive. Dr. Alderson, Ms. Regan, Mr. Martellet, and Dr. Hosken are or were employed by PATH, a collaborator on MenFive’s development. Drs. Pisal and Dhere are co-inventors on 20 patent applications emerging out of in-house MenFive research at SIIPL.

Patient consent statement

This study is a review and did not directly involve human participants.