Successful African introduction of a new Group A meningococcal conjugate vaccine: Future challenges and next steps

ABSTRACT

The introduction of a new Group A meningococcal conjugate vaccine, MenAfriVac^R, has been a important public health success. Group A meningococcal meningitis has disappeared in all countries where the new Men A conjugate vaccine has been used at public health scale. However, continued control of Group A disease in sub-Saharan Africa will require that community immunity against Group A meningococci be maintained. Modeling studies have shown that unless herd immunity is maintained Group A meningococcal disease will return.

To ensure that African populations remain protected birth cohorts must be protected with an EPI formulation of MenAfriVac^R (5 mcg) given at 9 months with Measles 1. In addition, populations born after the initial 1-29 year old campaigns and consequently not yet immunized with the new Men A conjugate vaccine, will have to be immunized in country-specific catch-up campaigns. Countries with poor EPI coverage (Measles 1 coverage < 60%) will likely need quinquennial vaccination campaigns aimed at covering 1-4 year olds. Implementing these strategies is the only sure way of ensuring that Group A meningococcal meningitis epidemics will not recur.

A second problem that requires urgent attention is the challenge of dealing with Non-A meningococcal meningitis epidemics in sub-Saharan Africa. Groups C, W and X meningococci are well-established circulating strains in sub-Saharan Africa and are responsible for yearly focal meningitis epidemics that vary in severity and remain unpredictable as to size and geographic distribution. For this reason, polyvalent meningococcal conjugate vaccines that are affordable and appropriate for the African context must be developed and introduced. These new meningococcal vaccines when combined with more affordable pneumococcal conjugate vaccines offer the promise of a meningitis-free Sub-Saharan Africa.

Introduction

Sub-Saharan Africa has long been an important locus for epidemics of meningococcal meningitis. Until recently episodic major waves of Group A meningococcal meningitis were superimposed on unpredictable focal epidemics in so-called “meningitis belt” countries that extend from Senegal and The Gambia to Ethiopia. These recurrent meningitis epidemics have caused untold misery.

The Meningitis Vaccine Project, a Gates Foundation funded partnership between WHO and PATH, was created in June 2001 to develop new Group A meningococcal conjugate vaccines to solve this problem. From 2003 to 2010 the partnership worked closely with the Serum Institute of India to develop, test and license a new Group A conjugate vaccine. The development, clinical testing and licensure of this vaccine has been described in detail in several publications.^1-3 In short, the new MenA conjugate vaccine, PsA-TT, incorporated 10 mcg of Group A polysaccharide that was linked to tetanus toxoid using a conjugation method developed at the CBER laboratories at the US Food and Drug Administration, Bethesda.⁴ Final formulation of the vaccine resulted in a lyophilized cake with Thimerosol as a preservative. The diluent was adjuvanted with aluminum phosphate and the vaccine was shown to be heat stable and could be used outside the cold chain up to 4 days.⁵

The vaccine was extensively tested in clinical trials in India and West Africa (Senegal, Mali and Ghana). Study results showed that the new Men A conjugate vaccine was superior to Group A polysaccharide vaccines and generated robust bactericidal antibody titers that persisted. A license application was submitted to the Drugs Controller General of India in April 2009 and an Indian export license was granted in December 2009. A prequalification dossier was submitted to WHO in January 2010 and the vaccine was prequalified by WHO in June 2010.

Over a seven-year period (2010-2017) more than 270 million Africans between the ages of 1 and 29 years of age received a dose of MenAfriVac in large vaccination campaigns that were well received by local populations. The vaccination campaigns were usually done in the 4^th quarter of the year and just ahead of the annual meningococcal outbreak season which began in January and ended in May.

The progressive coverage of meningitis countries used a WHO district prioritization tool that standardized district meningitis risk while establishing vaccine demand forecasts.⁶ Validated protocols assisted countries in the planning for MenAfriVac^R campaigns and facilitated planning and funding applications. The prioritization exercise ensured that local information was integrated into the planning document. Sound planning was necessary to ensure that the quantity of vaccine that was available from the Serum Institute of India was harmonized with the introduction plan that respected geographic contiguity and district risk. The process worked well and the plans that flowed from the country and WHO risk assessments resulted in a series of vaccination campaigns that respected the priorities established in the risk reviews.⁶

Herd immunity rapidly developed after mass immunizations with the cessation of circulation of Group A meningococci and the disappearance of Group A meningococcal infections. This rapid success has generated two important new questions:

• 1)how do African countries ensure that the successful elimination of Group A meningococcal infections is maintained and
• 2)what should be done do combat the non-A meningococcal epidemics.

Implementing follow up plans to maintain community immunity against Group A meningococci is a timely and important question because the decisions that are taken over the next few years by African Ministries of Health, WHO, UNICEF and GAVI could put at risk the major success that has been achieved to date. Furthermore, there is uncertainty about how to best manage non-A meningococcal epidemics. In Africa each meningococcal meningitis outbreak carries with it the potential threat of a major epidemic since the basic climatic conditions that favor epidemic spread of meningococcal infections in Africa have not changed.

We explore these themes to highlight the public health decisions that need to be taken over the next few years to ensure that the successful elimination of Group A meningococcal epidemics not only continues but is seen as an initial step towards achieving a more comprehensive public health goal – the elimination of bacterial meningitis as a public health problem in Africa.

The MenAfriVac^R success in Burkina Faso as an example of the power of herd immunity

On December 6, 2010 a new Group A meningococcal conjugate vaccine, MenAfriVac^R, was introduced in Burkina Faso and over the next 10 days 10.8 million Burkinabes between the ages of 1 to 29 years received an intramuscular dose of the vaccine.⁷ Later vaccine coverage assessments indicated that almost 96% of all 1 to 29 year olds received the vaccine.

The high vaccine acceptance was facilitated by a communication campaign that was begun in April 2010 and that bore important dividends.⁸ Post-immunization surveys showed that social and media mobilizers accounted for 65 percent of the information sources followed by health agents (24%) and religious leaders (11%) and that 98 percent of vaccine recipients (or their surrogates) were aware that they were being immunized with a vaccine to prevent meningitis.⁸

An important ally in the successful campaign was the President of Burkina Faso, His Excellency Blaise Compaore. In 2007, President Compaore was approached by Dr. Luis Sambo, the then WHO AFRO Regional Director, and he was asked to serve as an African “Patron” to lead the advocacy for the new Men A conjugate vaccine. As the MVP “Patron” the Burkina Faso President held meetings with Dr. Sambo that were well publicized in the media. In September 2008 during the 58^th session of the WHO Regional Committee, African Ministers of Health unanimously adopted the Yaounde Declaration that committed them to introduce a new and promising Group A meningococcal conjugate vaccine.⁸

The public health impact that followed the introduction of MenAfrivac was as dramatic as it was sudden; Group A meningococcal meningitis disappeared.⁹ Table 1 summarizes data on reported cases of meningitis in Burkina Faso from 2007 to 2017 and details the impact on Group A meningococcal meningitis that followed introduction of the vaccine. From 2006 to 2008 Burkina Faso suffered a major epidemic of Group A meningococcal meningitis with about 45,000 cases over this time period. In December 2010 all 1-29 year olds were immunized and in 2011 reported meningitis cases fell dramatically and Group A Neisseria meningitidis spinal fluid isolates disappeared. This trend has continued, from 2011 to 2017 Burkina Faso reported eight cases of Group A meningococcal disease; of the eight Group A cases only one person (2015 case in a 7 year old) had been vaccinated. The child's mother reported that the child received a dose of MenAfriVac during the 2010 MenAfriVac campaign. To date, this case is the only documented vaccine failure that has been reported after receipt of a dose of MenAfriVac. Despite intense surveillance that included PCR testing of all spinal fluid specimens since 2011 no cases of Group A meningitis were identified in 2012-2014 and 2016-2017.

Table 1.

Impact of MenAfriVac on isolation of Group A Neisseria meningitidis from spinal fluid specimens (2005- 2017) in Burkina Faso.^*

Year	Reported meningitis cases	CSF specimens sent to laboratory	% Group A in positive CSF specimens
2005 (wk 18)	3,626	118	27.1
2006	19,134	1997	84.6
2007	26,878	417	91.1
2008	10,401	241	79.2
2009	4,723	275	30.1
2010	6,732	469	24.9
Introduction of MenAfriVac in December 2010
2011	3,875	3125	0.1
2012	6,797	3297	0.0
2013	2,512	1104	0.0
2014	3,476	2391	0.0
2015	2,927	1781	0.5
2016	2,645	1857	0.0
2017 (wk 23)	1,729	945	0.0

^*data from WHO/IST-WA, Meningitis Weekly Bulletin. 2005-2017.

Detailed meningococcal carriage studies were done in association with the introduction of MenAfriVac.¹⁰ The results were clear cut; while baseline carriage of group A meningococci was low (about one half percent) the Group A carriage rate fell to zero after vaccination in serial carriage studies that were done over the next year. These data were consistent with the achievement of herd protection. The presence of herd immunity against Group A Neisseria meningitidis predicted that the overall public health effect after the introduction of MenAfriVac would be substantial. This prediction was realized as more meningitis belt countries completed their campaigns and cases of Group A meningococcal disease disappeared throughout the meningitis belt. During the 2017 epidemic season only 2 cases of Group A disease were noted among the 350 to 400 million persons residing in the meningitis belt.¹¹ Since its introduction at public health scale it is estimated that between 250-500,000 cases of Group A meningococcal meningitis have been prevented.

What will happen over the next 20 years?

Two modeling studies have examined long term public health outcomes after the introduction of MenAfriVac.^12,13 Both models used parameters that were derived from African sources and described (1) the annual incidence of meningitis before the introduction of the Men A conjugate vaccine; (2) the impact of mass vaccination campaigns in 1-29 year olds with high coverage and (3) compared the long term effects with a cessation of use of the new vaccine with a variety of preventive strategies. Both models predicted that the initial mass vaccinations in 1 to 29-year-olds with high acceptance rates would lead to control of Group A infections for 10 to 20 years. However, unless immunizations were provided to newborn birth cohorts all countries would face major Group A meningitis epidemics within 15 to 20 years as the unprotected newborn cohorts were added to the population. Both models predicted that unless newborn cohort were protected Group A meningococcal outbreaks would return with tens of thousands of cases of meningitis.

In 2013 WHO's SAGE committee reviewed the problem and recommended that infants from meningitis belt countries receive a single dose of the pediatric formulation of MenAfriVac (5 mcg) along with Measles and Yellow Fever vaccines at 9 months and that persons born after the initial 1-29 year old campaigns be vaccinated in mini campaigns.¹⁴ Modelers then explored the effects of introducing an EPI dose of MenAfriVac at 9 months with and without the 1-4 year old catch up campaigns. The combined preventive strategies (EPI dose plus unvaccinated 1-4 year olds) proved to be the most effective strategy in predicting long term control of Group A disease.¹² Countries with Measles 1 vaccine coverage less than 60 percent could also consider conducting quinquennial campaigns aimed at providing all 1-4 year olds with a dose of MenAfriVac vaccine.

There are limitations in any modeling exercise. The long-term protection from a single dose of MenAfriVac remains to be determined. Follow-on serologic studies at seven years have shown robust SBA titers, an observation consistent with the supposition that long term protection is likely to extend to 10 to 15 years. Nonetheless, both papers agree that their models predict the return of Group A meningococcal meningitis epidemics unless community immunity is maintained by providing the Men A conjugate vaccine as a standard EPI antigen at 9 months.

What to do about African non A meningococcal epidemics?

Scope and extent of non A meningococcal disease

The elimination of Group A meningococcal infections has helped to clarify the extent of non A meningococcal disease in Africa. Table 2 summarizes the distribution of spinal fluid isolates in Burkina Faso and Niger after the introduction of the Men A conjugate vaccine. Both Niger and Burkina Faso have excellent meningitis surveillance with comprehensive microbiologic capabilities. About half of all suspect cases of meningitis had a lumbar puncture and of the spinal fluid specimens that were submitted for laboratory studies about 40 percent were positive after PCR testing.

Table 2.

Reported cases of meningitis and distribution of spinal fluid isolates in Burkina Faso and Niger from 2011 to 2016.^*

					Positive samples
Burkina Faso	Year	Reported cases	No. CSF to lab.	% to lab	Men A	Men C	Men X	Men Y	Men W	Pneumo
	2011	3875	1214	31	4	0	153	1	99	713
	2012	6957	3297	47	0	0	138	1	704	236
	2013	2917	1104	38	0	0	15	0	165	244
	2014	3476	2504	72	0	0	2	0	208	497
	2015	2927	1781	61	4	7	5	0	242	460
	2016	2645	1857	70	0	13	31	0	132	474
Niger
	2011	1214	883	73	4	0	1	0	368	59
	2012	271	271	100	0	0	0	0	11	24
	2013	311	209	67	0	0	0	0	0	24
	2014	327	240	73	0	8	0	0	16	26
	2015	8579	4606	54	0	1183	1	0	206	123
	2016	1973	1705	86	0	312	15	0	25	75

^*data from WHO/IST-WA, Meningitis Weekly Bulletin, 2011-1016.

The data show that meningococcal serogroups C, X and W are well established in both countries. The C epidemic strain was initially identified in 2014 in Nigeria and spread to Niger to cause the 2015 epidemic. The 2015 Group C epidemic in Niger was severe with over 8,000 cases primarily located in the southwestern corner of Niger.¹⁵ In 2017 the C strain expanded in northwestern Nigeria and caused over 10,000 cases.¹⁶ Group W meningococci regularly caused focal epidemics from 2011 to 2016 in Burkina Faso and Niger.

Worth remembering is the epidemic potential of the non A strains. The 2002 W epidemic in Burkina Faso caused over 10,000 cases and the C outbreaks in Niger (2015) and Nigeria (2017) are reminders that nonA meningococcal meningitis epidemics in sub-Saharan Arica have the potential to cause thousands of cases of meningitis for reasons that are still not well understood.

Managing non A epidemics has proven to be challenging. Over the last 30 years reactive vaccination strategies have been used to control meningitis outbreaks in the African meningitis belt. WHO serves as the secretariat for the International Coordination Group (ICG) which manages epidemic response activities in collaboration with African Ministries of Health.¹⁷

WHO has established protocols on how to deal with meningitis epidemics. When district meningitis cases exceed a threshold of 10 cases per 100,000 the district reaches “epidemic status”. Once the infecting strain has been identified a country request for meningitis vaccine is sent to the ICG. The ICG has access to a stockpile of meningitis vaccines that are stored with vaccine manufacturers. Orders are placed and vaccines are then shipped to the Ministry of Health (MOH) of the affected country and the MOH along with regional and local health agencies organize district vaccinations in 1-29 year olds. Coverage assessments are done to gauge the quality of the vaccination response. Given the long history of epidemic meningitis in sub-Saharan Africa these “reactive” vaccination campaigns are expected by populations.

Review of the public health impact of these reactive campaigns suggests that they have not been very successful. There are several steps that are required in order to complete a reactive vaccination strategy. These steps take time and a recent analysis indicated that that it took a little over one month from the onset of an African epidemic to the time vaccine was made available at the district level. Another 14 days must be added to ensure that protective antibody responses have been generated after immunization. This six week timeline is problematic given that focal African meningococcal epidemics are largely over in six weeks. At best and with the constraints as they stand in 2017 only about 10-15 percent of epidemic cases are preventable by reactive vaccination campaigns.

Significantly decreasing the time from the onset of a meningitis epidemic to the in-country delivery of vaccine is not easy because of the need to identify the infecting strain so that the proper vaccine may be recommended. Meningitis epidemics can occur anywhere and an important challenge to public health staff is getting sufficient spinal fluid specimens to a qualified laboratory so that accurate testing can take place. For example, in Nigeria only physicians are allowed to perform lumbar punctures hence there are few spinal fluids to be tested. What we do know is that nonA meningitis epidemics will occur every year between January and May somewhere in sub-Saharan Africa and that occasionally, as was the case in Burkina Faso in 2002, Niger in 2014 and Nigeria in 2017, become big epidemics.

Need for an Africa-specific polyvalent meningococcal conjugate vaccine

Using grant support from the Department for International Development, UK, PATH and the Serum Institute of India are currently testing a multivalent ACYWX conjugate vaccine that was developed specifically for African meningitis belt countries. The vaccine has recently completed Phase 1 study in the US and Phase 2 and 3 clinical studies in Africa and India are currently being planned. Having an affordable pentavalent (ACYWX) conjugate vaccine could greatly expand strategies that could be used to reduce and potentially eliminate nonA meningococcal epidemics in Africa.

By example, the success of MenAfriVac^R in establishing herd immunity after campaigns that targeted 1-29 year olds strengthens the possibility that a similar approach using a polyvalent meningococcal conjugate vaccine might well have a similar impact on non-A meningococcal disease in meningitis belt countries. Eliminating all non-A meningococcal disease is an attractive goal and would appeal to meningitis hyperendemic countries like Burkina Faso, Mali, Niger, northern Nigeria, Chad and parts of Ethiopia where non-A meningitis epidemics are regularly reported.

Using a polyvalent meningococcal conjugate vaccine to prevent colonization and establish herd immunity is evaluable. During the testing and introduction of MenAfriVac^R meningococcal carriage studies were done in Burkina Faso and they showed carriage rates of encapsulated meningococci in the range of 4–7%.^10,18 Hence, carriage studies could be done in populations that received and did not receive a dose of a new polyvalent (ACYWX) vaccine. If the polyvalent vaccine behaves like MenAfriVac^R, meningococcal carriage rates in vaccinated populations should quickly fall and stay at very low levels. More precise carriage studies could study the effect of immunizing different age groups to better define what groups need to be covered in “catch up” campaigns in order to create herd immunity. In short, the lessons from the MenAfriVac work could serve as a clear pathway for exploring how effective a polyvalent meningococcal conjugate vaccine could be in inducing herd immunity.

Table 3 describes possible effects of reactive and preventive strategies using a polyvalent meningococcal conjugate vaccine. The proposed outcomes assume that Group A meningitis is controlled and that MenAfriVac is being given as an EPI antigen at 9 months along with measles 1.

Table 3.

Projected effect of vaccine strategies using MenAfriVac and a polyvalent (ACYWX) meningococcal conjugate vaccine on African meningococcal meningitis epidemics.

Vaccine strategy			Effect on A and non A N mening. epidemics
EPI vaccine Routine	Catch up campaigns	PVMC* Vaccine in ICG stockpile	Men A	Non A
MenAfriVac	1-29 years (finished)	Yes	No A epidemics	Epidemics continue
PVMC vaccine	None	Yes	No A epidemics	Non A epidemics continue but decrease after 10–15 years
PVMC vaccine	1-29 years**	None necessary	No A epidemics	No non A epidemics

^*PVMC – polyvalent (ACYWX) meningococcal conjugate vaccine

^**initial campaign giving a single dose of ACYWX conjugate vaccine to 1–29 year olds to establish herd immunity

Assuming that the polyvalent ACYWX conjugate vaccine blocks colonization when the vaccine is given to 1–29 year olds all non A meningococcal infections would disappear. Such an impact is likely to be cost effective since it would eliminate all short and long term clinical costs associated with meningococcal infections as well as the costs associated with mounting reactive vaccination strategies.

A second strategy to deal with Non A meningococcal infections might consist of substituting the polyvalent ACYWX conjugate vaccine for MenAfriVac as the recommended EPI vaccine. If the polyvalent vaccine induces robust long-lasting immunity the protected population would grow over time and after 15 to 20 years herd protection may occur. Nonetheless, it is important to note that epidemics of non A meningitis would continue to occur during the 15-20 year interval and these epidemics could generate a perception of poor performance of the vaccine. Gradual immunization of a population with an ACYWX conjugate vaccine through EPI immunizations will likely generate herd protection that is not as robust as that observed with rapid immunization of a large segment of the population.

Whatever vaccine strategy is used, the evaluation of the ACYWX conjugate vaccine impact will be easily seen through the analysis of routine meningitis surveillance data. Hence, investments to maintain comprehensive meningitis surveillance with associated laboratory costs must continue given the obligation to have a clear understanding of the impact of introducing a new vaccine on the epidemiology and etiology of meningitis in Africa.

Lastly, the availability of an affordable, effective multivalent meningococcal conjugate vaccine should greatly facilitate reactive campaigns. Because an ACYWX vaccine covers all currently circulating meningococcal strains in Africa the vaccine could be stored in African sites which could result in speedier access to the vaccine.

Important unanswered questions include clearly identifying the age group that would need to be vaccinated to achieve herd immunity using a polyvalent meningococcal conjugate vaccine and whether booster doses would be necessary.

Summary

The success of MenAfriVac^R in generating herd immunity and eliminating Group A epidemics in sub-Saharan Africa has broadened perspectives on how best to deal with non A meningococcal infections. If new polyvalent meningococcal conjugate vaccines are effective in eliminating meningococcal carriage the elimination of all meningococcal infections in sub-Saharan Africa becomes a realistic possibility.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed