Developmental strategy for a new Group A meningococcal conjugate vaccine (MenAfriVac^R)

ABSTRACT

Until recently, periodic Group A meningococcal meningitis outbreaks were a major public health problem in the sub-Saharan Africa. In 2001, the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization (WHO) and PATH, a Seattle-based NGO, and the Serum Institute of India Pvt Ltd (SIIPL) initiated discussions aimed at establishing a collaboration to develop a Group A meningococcal conjugate vaccine for this unmet medical need. Over the next 8 years the partnership made countless strategic decisions about product characteristics, raw materials, potential target populations, geographic prioritization and affordability of the vaccine to name a few. These decisions evolved into detailed plans for preclinical development, extensive field trials in Africa and India and a focused regulatory strategy specific for the Men A conjugate vaccine. Important characteristics of the process included, flexibility, transparency andeffective partnerships that included public agencies as well as private companies in Africa, Europe, the United States and India.

Introduction

Until recently, epidemic Group A Neisseria meningitidis meningitis was a major public health problem globally and especially in sub-Saharan Africa. The scope of these meningitis outbreaks in this region has been well documented.¹ The reactive vaccination campaigns using meningococcal polysaccharide vaccines that were mounted in response to these epidemics did not prevent the recurrence of these epidemics² and there was a pressing need for a new conjugate Group A vaccine which would be immunogenic in young children and which would induce herd immunity. Given the immediacy and magnitude of the problem the Gates Foundation awarded a grant of $US 70 million in June 2001 to establish the Meningitis Vaccine Project (MVP), a partnership between PATH, a Seattle-based NGO and the World Health Organization, with the goal of developing, testing, licensing and introducing a new Group A meningococcal conjugate vaccine.³

In late 2001, Serum Institute of India Pvt Ltd (SIIPL) was first approached by the MVP to explore whether SIIPL would be interested in partnering with MVP todevelop this new vaccine. SIIPL indicated an interest and work began. In 2003 MVP had acquired a conjugation technology from the US Food and Drug Administration. Some expertise in making a HiB conjugate vaccine was already present at SIIPL but the new FDA technology required that SIIPL scientists learn this technique at FDA during the 2003 winter holidays in Bethesda, Maryland.^4–8

Two raw materials were necessary, vaccine grade Group A polysaccharide and a carrier protein. A contract between MVP and SyncoBioPartners, a Dutch contract manufacturing company, provided for quantities of fully qualified Group A meningococcal polysaccharide that were used for the preclinical development work. SIIPL's tetanus toxoid (TT) was chosen as a carrier protein⁶

Vaccine development

By 2006 SIIPL scientists had developed and scaled up a new Group A meningococcal conjugate vaccine. This speedy development was possible because the FDA conjugation technology was already available as well as ample quantities of Group A polysaccharide and purified tetanus toxoid. Facilitating this effort was the deep experience of SIIPL scientists in manufacturing large volumes of EPI vaccines like measles, BCG, and DPT. Because no WHO technical specifications were available for a Group A meningococcal conjugate vaccine, SIIPL relied on a consortium of dedicated international consultants who worked diligently with SIIPL scientists to address the many technical problems that arose during the development process.⁶

Discussions with African public health experts in 2001 and 2002 clearly indicated that the vaccine had to be “affordable” if its use were to continue beyond the initial splurge of donor support for the new vaccine. Health ministers from meningitis belt countries indicated that the per dose price had to be less than $US 0.50 to ensure that the new vaccine use would be sustainable.⁹

To keep the price manageable a multidose presentation was chosen. Moreover, since the basic target of the MenA conjugate vaccine was going to be use in mass immunization campaigns for individuals between 1–29 years of age a multidose presentation made it operationally easier to ship vaccines while also decreasing the impact on already strained cold chain capacity in African meningitis belt countries.

The form of the vaccine (ready-to-use liquid form or as a lyophilized powder) was also vigorously debated. Since the cold chain capacities in many developing countries are limited and since the mass immunization campaigns were to unfold in remote areas, it was decided that a stable lyophilized presentation will be more suitable, especially during the hot seasons.

Another important issue was the choice of diluent. Usually sterile water for injection or sodium chloride are used as diluents for lyophilized injectable vaccines.¹⁰ Because of the importance of inducing a robust immune response after a single dose an aluminum adjuvant was added to the diluent. In preclinical animal studies adjuvanted Men A vaccine was more immunogenic than unadjuvanted vaccine.

There was also debate on the use of a preservative. Since a multidose presentation was chosen,there were experts that argued in favour of including a preservative. On the other hand there was no precedent for using a preservative in lyophilized vaccines that were available in multi-dose presentations like measles and BCG vaccines.¹¹ In the end and after consultations with countries, WHO and UNICEF it was decided that since the vaccine was going to be used in mass immunization campaigns in remote areas that there could be errors in vaccine preparation, which could potentially lead to contamination and subsequently severe adverse events. Such accidents have been reported with multidose measles vaccines.^12,13 Therefore, it was decided to add thiomersal as a preservative in the diluent.

As regards a carrier protein, there were several choices that were available such as tetanus and diphtheria toxoids and CRM 197 since these proteins had already been used in licensed conjugate vaccines. TT was a particularly attractive carrier protein for the new Men A conjugate vaccine. TT was already being manufactured at a large scale at SIIPL and experimental batches of the Men A conjugate vaccine that used TT as a carrier protein showed excellent immune response. Lastly, neonatal tetanus is still an important public health problem in sub-Saharan Africa.¹⁴ Since TT when used as a carrier protein induces an immune response to TT the choice of TT as a carrier proteincould confer a public health good, a supposition that has now been confirmed.¹⁵

As previously noted the meningococcal A polysaccharide was initially procured from SyncoBioPartners who later transferred the technology for the manufacture and purification of the Men A polysaccharide to SIIPL. As a result SIIPL developed its in-house capacity to produce polysaccharide at a large scale which not only ensured timely supplies, but also significantly decreased the cost of production.

The target population for this vaccine was driven by the disease epidemiology and the immunization strategies. The data from various studies had clearly shown that the most vulnerable population for meningitis A outbreaks was 1 to 29 years.¹⁶ Since this age group does not fall under the routine EPI-based immunization strategies the only way to reach them would have been to conduct mass immunization campaigns. The campaigns would also ensure immunization of the target populations in the shortest possible time. Therefore, the first target use of the vaccine was going to be mass immunization campaigns in 1 to 29 years age group in the meningitis belt.

WHO and country epidemiologists reasoned that herd immunity might well follow the mass immunization campaigns. However, future birth cohorts would remain susceptible to Group A meningococcal disease if they were not immunized and there was every likelihood that over time Group A outbreaks would recur. Therefore, it was important to ensure that the MenAfriVac clinical development plan also include study of a specific EPI-based formulation (5 mcg) vaccination using a pediatric formulation (5 mcg)in order to facilitate introduction of MenAfriVac into the routine EPI schedule.

The vaccine had undergone substantial reproduction toxicities studies in animals. The data had shown that the vaccine was neither teratogenic nor did it affect male or female fertility. Nonetheless, as a matter of caution during the clinical trials, pregnancy was an exclusion criterion. However, during subsequent MenAfriVac mass immunization campaignsmany pregnant women inadvertently received the Men A conjugate vaccine. These women were carefully followed and there was no adverse effect on the foetal outcome. Therefore, in 2012 WHO recommended that MenAfriVac could be used in pregnant women.¹⁷ In addition, subsequent clinical studies showed that MenAfrivac resulted in induction of high tetanus immunity.¹⁵

Since early days of the project, MenAfrivac was conceived as a single dose vaccine for the 1–29 year old mass immunization campaigns. This was important because of the logistic and financial problems associated with providing multiple doses of vaccine in mass immunization campaigns.

Since the vaccine was basically meant for the sub Saharan Africa, it was appropriate that the bulk of the clinical trials be conducted in that region. However, the vaccine was manufactured in India and it required manufacturing license from the Indian NRA, the Drugs Controller General of India (DCGI). The Men A conjugate vaccine project was discussed with Indian regulatory officials and the DCGI suggested that the first-in-human clinical trial should be conducted in India. As a result the Phase I trial was conducted in India and after the safety was established in Indian adults, further clinical trials were conducted in Africa. Based on the African data, the vaccine was licensed initially for export only. Two more studies were conducted in India to assess responses in the Indian population and after completion of the studies an Indian license was also granted.^4,18

The clinical studies compared the Men A conjugate vaccine to AC and ACYW polysaccharide vaccines. Although the first quadrivalent meningococcal conjugate vaccine against ACYW groups Menactra, had been licensed by then in USA the standard of care in meningitis belt countries was to use polysaccharide vaccines.

The clinical trials studied immune responses, safety and tolerability of the vaccine. A Phase II study in toddlers also demonstrated that the vaccine was immunogenic in the under 2 population, had excellent immune persistence as well as boostability of the response.^19–21

For introduction in routine immunization programs two studies were conducted in infant populations, which assessed different strengths (10 µg / 5 µg / 2.5 µg), different number of doses (2 doses / 1 dose) and different time points (14 weeks / 9 months / 12 months / 15 to 18 months). These studies demonstrated that infants required 5 µg dose and 2 doses if the vaccination was initiated at 14 weeks and a single dose if it was initiated at 9 months of age. The studies also demonstrated that the vaccine did not interfere with the immune responses of concomitant EPI vaccines like DPT, Hepatitis B, Hib, OPV, measles, rubella and yellow fever vaccines (Unpublished data).

As per WHO requirement, it was necessary that the consistency in the production should be demonstrated not only in terms of the CMC characteristics, but also in terms of immune responses in clinical studies. Therefore, one Indian study specifically assessed lot-to-lot consistency of the immune response mounted by three consecutive GMP lots of the vaccine in the 5 to 10 years of age group.

Following the successful completion of clinical studies and licensure, the vaccine was eventually launched in three mass immunization campaigns in 2010. Since then the vaccine has been extensively used in various meningitis belt countries. It has shown dramatic impact on the meningitis A incidence and the disease has been eliminated from those countries. Only a single vaccine failure has been documented.²² After use in more than 260 million people in the last 7 years, no safety issues have been identified.

Now that Group A meningococcal meningitis has been eliminated from many of these countries, meningitis outbreaks caused by other groups of Neisseria meningitis like C,W& X have gained prominence. As a logical “next step”, SIIPL has developed the world's first pentavalent meningococcal vaccine targeted against A,C,Y,W & X groups. The vaccine has undergone Phase I clinical trial in USA and now is poised to enter further clinical studies in Africa and in India.

Of the many lessons that were learned during the development process there were three that stood out:

• 1.Clarity of purpose: The development of MenAfriVac included the participation of over 40 groups which included private companies, international and national public health agencies, academia, regulatory agencies, country-specific public health agencies and non-governmental organizations, to name a few. Coordination of these partnerships was no simple matter but it was greatly facilitated by a single goal – the elimination of epidemic Group A meningococcal meningitis. The fact that all partners were committed to reaching this goal allowed for a level of comity that was powerful and often surprising.
• 2.Availability of information on Group C meningococcal conjugate vaccines and their impact in the UK and the Netherlands: MVP benefitted hugely from the quality and the quantity of information that was made available as a result of the development and introduction of three Group C meningococcal conjugate vaccines in the United Kingdom and the subsequent introduction of a Group C conjugate vaccine in the Netherlands.^23,24 The development of the Group C vaccines shed important information on conjugation chemistry and the UK Men C carriage studies provided a rich source of information that MVP used to predict that herd immunity would ensue after the introduction of a Men A conjugate vaccine in campaigns targeting 1–29 year olds.^25,1
• 3.Up front funding from the Gates Foundation: MVP funding was unusual. In June 2001 a10 year grant of $US 70 million created the PATH/WHO partnership that was the MVP. The Gates Foundation funding was provided up front and the earned interest on the unspent funds was added to the grant. The guarantee of long term funding allowed MVP to explore different ways making the Men A conjugate vaccine. Some of the initiatives were major successes like the transfer of the FDA conjugation chemistry to SIIPL while other initiatives failed.⁹ The important point was that with assured funding in place, MVP could take a longer view of how best to reach the project's goal. The revised approach emphasized African public health needs and the economic realities of providing a new vaccine to meningitis belt countries. In the end, the Africa focus created new opportunities that led to the successful MVP/SIIPL partnership.

Conclusion

Any new vaccine development requires many strategic decisions that are based on the disease profile, target population and the economics of immunization. A great deal of debate and reflection infused the developmental strategies of MenAfriVac which involved brainstorming of not only SIIPL, PATH, WHO scientists, but many independent International experts and institutions. Careful discussions in a supportive and flexible environment were of paramount importance in ensuring that the Men A conjugate vaccine met expectations and was broadly available to meningitis belt countries.

Disclosure of potential conflicts of interest

The authors are employed by SIIPL, the manufacturer of MenAfriVac.

Acknowledgments

The authors gratefully acknowledge the enormous contributions made by team members from SIIPL, PATH, WHO/HQ, WHO/AFRO, the Gates Foundation, CBER/FDA, NIBSC/UK, African and Indian clinical trial sites, CDC/Atlanta, PHE/UK and three long term MVP consultants, Costante Ceccarini, Neil Ravenscroft and Jean Petre.