Vaccines for the prevention of meningococcal capsular group B disease: What have we recently learned?

Abstract

Meningococcal disease remains a feared and devastating cause of sepsis and meningitis. Disease incidence is highest among infants and children although a significant burden of disease is experienced by adolescents, young adults and those with specific risk-factors. Prevention of disease against capsular groups A, C, W and Y; 4 of the 5 most pathogenic groups is achievable using capsular polysaccharide vaccines. It has only recently been possible to provide protection against capsular group B (MenB) strains following the licensure of a 4 component group B vaccine (4CMenB) in Europe in 2013. Following licensure, 4CMenB has been used in specific at-risk groups and in response to outbreaks of MenB disease. The largest outbreak interventions have been in students at 2 universities in the United States and for all individuals aged 2 months to 20 years of age in Quebec, Canada. The vaccine was recommended in February 2014 for implementation into the UK infant schedule at 2, 4 and 12 months of age, although it has taken over 12 months to resolve procurement discussions to enable implementation. The UK recommendation incorporates prophylactic paracetamol with infant doses when 4CMenB is administered concomitantly with routine vaccines. This is based on recent data demonstrating the ability of paracetamol to reduce fever rates to background levels without impacting immunogenicity. Post-implementation surveillance will be important to provide vaccine efficacy data as this was not possible to determine in pre-licensure studies due to the relative infrequency of MenB cases.

Keywords:

• 4CMenB
• Group B
• meningococcal
• vaccine

Introduction

The Gram-negative bacterium Neisseria meningitidis is the causative organism of meningococcal disease which remains a significant cause of morbidity and mortality globally. The organism colonises the human nasopharynx and is carried by 10–40% of individuals at any one time, in most cases asymptomatically.¹ Transmission occurs between individuals via droplet spread during close contact which can then occasionally result in invasive disease following translocation across the respiratory epithelial barrier. Disease can initially present with indistinct and general symptoms before rapid progression to sepsis or meningitis which can occur either singularly or collectively. The greatest burden of disease is observed in infants, young children, adolescents and those with specific risk factors such as complement deficiency and asplenia, irrespective of age.²

The organism is classified via differences in the polysaccharide capsule into 12 groups, of which A, B, C, W and Y collectively account for almost all cases of disease.³ In the UK, control of group C disease was achieved following the introduction of the monovalent group C glycoconjugate vaccine in 1999,⁴ resulting in group B (MenB) now being responsible for the majority of disease.⁵ A vaccine to provide protection against MenB strains was licensed in Europe in 2013.⁶ and recommended for implementation into the UK infant schedule by the Joint Committee on Vaccination and Immunisation (JCVI) in February 2014.⁷ Despite this recommendation, implementation has been delayed due to procurement discussions between the Department of Health and the manufacturer which have only recently been resolved in March 2015.

Meningococcal Vaccines

The purified capsular polysaccharides of meningococcal group A, C, W and Y have successfully been used to develop efficacious vaccines.² In the UK, the initial ‘plain’ polysaccharide vaccines have now been largely superseded by glycoconjugate formulations following the licensure of the first monovalent group C vaccine in 1999,⁴ and the first quadrivalent (group A, C, W and Y) vaccine in 2010.⁸ Attempts at producing a capsular polysaccharide vaccine for MenB have been unsuccessful due to its structure being antigenically similar to the human foetal neural cell adhesion molecule resulting in poor immunogenicity and the potential of autoantibody generation.² Vaccine developers have therefore focused attention on identifying conserved sub capsular vaccine candidates, which are present among all virulent meningococci and surface expressed.

The first successful vaccines developed to provide protection against MenB disease incorporated outer membrane vesicles (OMVs) from local outbreak strains in response to clonal epidemics in Norway, Cuba, Chile and New Zealand. Despite proven efficacy across all age groups, protection afforded by these vaccines is generally specific to the clonal outbreak strain due to the immunodominance of the PorA protein.² These vaccines are therefore unable to provide protection in regions such as the UK where epidemiology comprises diverse endemic MenB strains.

In order to develop a broadly protective vaccine against MenB strains, a new approach using the whole genome sequence of a single MenB strain to predict and identify surface expressed proteins was employed.⁹ A combination of in-vitro and in-vivo procedures were used to evaluate proteins for suitability as vaccine antigens and their ability to induce a protective bactericidal immune response. The outcome of these investigations were 3 core immunogenic proteins recombinantly expressed in Escherichia coli; factor H binding protein (fHbp), neisseria adhesin A (NadA) and Neisseria heparin binding antigen (NHBA). A final vaccine formulation was created by combining the 3 core recombinant proteins with OMVs from the New Zealand outbreak strain NZ 98/254 to result in a 4 component MenB vaccine (4CMenB).² Following the demonstration of the vaccines safety and immunogenicity, it was licensed in Europe in 2013 and then subsequently in other regions including Australia, South America and North America.^6,10

Unlike capsular polysaccharide vaccines the breadth of protection afforded by 4CMenB is independent of the capsule/group due to the use of sub-capsular antigens. The Meningococcal Antigen Typing System (MATS) was therefore developed to predict the vaccine strain coverage of 4CMenB by analyzing isolates recovered from disease cases. This method has been used to predict that 78% European and 73% of English and Welsh MenB isolates would be covered by 4CMenB.¹¹ Further studies on English and Welsh MenB isolates have confirmed the conservative nature of MATS and indicated that the vaccine strain coverage is 88%.¹²

Recommendations and Implementation of 4CMenB

Shortly after licensure of 4CMenB in Europe, the first recommendations for the vaccines use were in at-risk populations who were already recommended to receive meningococcal quadrivalent glycoconjugate vaccines.¹³ These groups included individuals with asplenia, splenic dysfunction, complement disorders, those receiving complement inhibitor therapy, certain travelers and laboratory workers. The vaccine was also concurrently recommended for use in clusters and outbreaks of MenB disease to prevent further cases and has been used in this role since becoming available.¹³

In the United States (US) during 2013, there were outbreaks of MenB disease at Princeton University and at the University of California Santa Barbara (UCSB) resulting in 13 confirmed cases including one fatality.¹⁴ As 4CMenB was not licensed in the US at that time, the vaccine was offered to students at the affected universities under the Food and Drug Administration expanded access investigational new drug protocol. Successful implementation resulted in 4,709 Princeton University students receiving both doses and 9,000 UCSB students receiving the first dose by February 2014.¹⁴ Initial results reported by the Center for Disease Control and Prevention indicate a safety profile similar to pre-licensure clinical trials.¹⁴

The first large scale public implementation of 4CMenB was commenced in Quebec, Canada during 2014.¹⁵ This was in response to an increase in MenB incidence, observed across all age groups. The Committee Immunization Quebec recommended the implementation of 4CMenB in all individuals aged between 2 months and 20 years covering the age groups most affected by the rise in disease incidence. One month following the implementation in June 2014, 43,740 individuals had received at least the first dose of vaccine. The active surveillance of safety undertaken by the Ministry of Health concluded that the vaccine is safe with an expected frequency of adverse events.¹⁵

In February 2014, the JCVI recommended 4CMenB for implementation into the UK infant vaccine schedule.⁷ The recommendation was for a 2 + 1 schedule to be given at 2, 4 and 12 months of age which consisted of one priming dose less than the licensed schedule in this age group. Cost-effectiveness formed a major component of evaluation and was one factor leading to recommendation of only 2 priming doses which were evaluated to be sufficiently immunogenic. There was no recommendation for use of the vaccine in older age groups such as in Quebec due to this being considered not cost-effective. This decision was partially informed by the lack of conclusive data on the ability of 4CMenB to impart herd protection by interrupting acquisition of carriage in adolescents and young adults.¹⁶ Despite the recommendation in February 2014, procurement discussions between the Department of Health and the manufacturer have taken over 12 months to resolve. These negotiations cantered on the price of the vaccine as emphasized by the JCVI which stated “the vaccine only demonstrated cost-effectiveness at a low price, plans for implementation should anticipate a sustainable and cost-effective program” when originally recommending the vaccine.⁷ During these discussions various groups including patient advocacy groups have been undertaking vigorous campaigning for a rapid resolution to procurement discussions. In March 2015 on the day before parliament was dissolved and shortly after GlaxoSmithKline had finalised its purchase of the vaccine from the previous manufacturer, an agreement on price was announced. Implementation commenced on the 1st September 2015.

Recent Developments and Considerations

Both pre-licensure studies and post-licensure surveillance in Quebec have identified an association between 4CMenB and fever, in infants when administered concomitantly with routine vaccines.^6,15 This association was identified early within the development cycle and a study was undertaken to investigate the use of prophylactic paracetamol in infants. This study confirmed that prophylactic paracetamol could reduce the rate of fever to the same level as when receiving routine vaccines only. The authors also concluded that local and systemic reactions were reduced in infants receiving paracetamol.¹⁷ Importantly, this study also confirmed that paracetamol administration had no impact on the immunogenicity of either 4CMenB or routine vaccines when administered concomitantly. Active surveillance in Quebec has confirmed the impact of antipyretic prophylaxis as fever was reported approximately 50% less frequently in children <2 years of age receiving such treatment.¹⁵ These data support the recommendation for paracetamol to offered prophylactically to infants when receiving 4CMenB and routine vaccines concomitantly.¹⁸ This does, however, raise issues about the logistics of providing paracetamol and its prescription by the National Health Service.

As 4CMenB contains meningococcal sub-capsular proteins, the protection afforded by the vaccine is not limited to MenB strains and is likely to extend to other non-MenB capsular groups. The JCVI considered this ‘additional’ coverage in conjunction with the introduction of a MenC adolescent/university booster as reasoning to remove the current infant MenC dose once 4CMenB and booster programmes are fully established.⁷ The NadA component of the vaccine is also likely to afford protection against the NadA harboured by the group W clone currently expanding in the UK. This particular clone is associated with a high case fatality rate and was responsible for 98 cases in England and Wales during the 2013/14 epidemiological year.⁵ In response, quadrivalent A, C, W and Y glycoconjugate vaccine has been recommended for all 14-18 year olds by the JCVI.¹⁹ This implementation is designed to provide direct protection of individual vaccinees but also generate indirect/herd protection covering other age groups such as infants. The use of 4CMenB in infants is expected to provide direct protection against this particular group W clone and will aid in overall disease control.

An alternative vaccine to provide protection against MenB strains was licensed on the 29^th of October 2014 in the US. The vaccine contains 2 variants of fHbp and was licensed for a 3 dose schedule in 10 to 25 year olds.²⁰ Pre-licensure studies have proven the vaccine safe and immunogenic in the age groups which it has been subsequently licensed for. The vaccine has been employed to combat recent MenB outbreaks at Providence College and in conjunction with 4CMenB at the University of Oregon during February and March 2015. Reports on the safety profile of the vaccine during these outbreaks and possible developments in the licensure of the vaccine in other regions are awaited.

Summary

We have now entered a new era for meningococcal vaccines following the licensure of firstly 4CMenB in multiple regions followed by the bivalent fHbp vaccine in the US. In the UK, 4CMenB is currently being used in at-risk populations and in response to MenB outbreaks. The population based implementation into the UK infant schedule has commenced following the successful resolution to procurement discussions. Implementation of 4CMenB into the schedule is via a 2 dose priming schedule at 2 and 4 months of age, with prophylactic paracetamol advised. This is in conjunction with a 12 month booster dose, designed to prolong antibody persistence and therefore direct protection.

The immunogenicity of 4CMenB has been proven in multiple studies but due to the relative rarity of MenB disease we have been unable to determine vaccine efficacy. This is only achievable following large post-licensure cohort/population based implementation. The first such data is likely to originate from Quebec, but enhanced surveillance systems are running following population based implementation of 4CMenB into the UK. The added complexity is that 4CMenB is expected to provide protection in 73–88% of cases,^11,12 i.e. not complete protection, a message which must be understood by healthcare professionals and the public alike.

Disclosure of Potential Conflicts of Interest

I have acted as a consultant, receiving travel support on behalf of Public Health England (PHE) for Baxter Biosciences, GlaxoSmithKline, Novartis Vaccines and Diagnostics and Pfizer. I have also undertaken contract research on behalf of PHE for Baxter Biosciences, GlaxoSmithKline, Merck, Novartis Vaccines and Diagnostics, Sanofi Pasteur and Pfizer.