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Prevention and control of meningococcal outbreaks: The emerging role of serogroup B meningococcal vaccines
Vaccine 33 (2015) 3628–3635
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Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Prevention and control of meningococcal outbreaks: The emerging role of serogroup B meningococcal vaccines Ernesto Oviedo-Orta a , Sohail Ahmed a , Rino Rappuoli a , Steven Black b,∗ a b
Novartis Vaccines, Siena, Italy Center for Global Health Cincinnati Children’s Hospital, 3333 Burnett Avenue, Cincinnati, OH 45229, USA
a r t i c l e
i n f o
Article history: Received 18 March 2015 Received in revised form 3 June 2015 Accepted 5 June 2015 Available online 17 June 2015 Keywords: Outbreak Meningococcal disease Meningococcal B disease Meningococcal B vaccines
a b s t r a c t Recently an investigational meningococcal B vaccine has been used in two college outbreaks in the US. This is the first time that a meningococcal B vaccine has been used for outbreak control in the US. However, strain specific vaccines for meningococcal B outbreaks have been developed in Norway, Cuba and to control a large prolonged outbreak in New Zealand. Although meningococcal disease is mostly endemic and baseline rates in the US have fallen over the past decade, outbreaks are not uncommon in the US and globally. In an outbreak, disease risk can rise 1000 fold or more and such outbreaks can last a decade or longer causing significant morbidity and mortality. Here we review the evolution of several serogroup B outbreaks, and, when applicable, the development and impact of meningococcal B vaccines to control these outbreaks. Prior to the availability of “broad spectrum” meningococcal B vaccines, vaccines developed to control meningococcal B outbreaks were strain specific. With the development of two newly licensed meningococcal B vaccines – a four component meningococcal B vaccine (Bexsero® , Novartis) and the two component fHBP vaccine (Trumenba® , Pfizer) that target a broad array of meningococcal B strains, there is now the potential to prevent outbreaks and as well as to shorten the delay between identification of an outbreak and availability of a vaccine. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction The epidemiology of a disease is often described as if the incidence and disease burden were both a steady state with age specific incidences being described. While this is largely true for diseases such as pneumococcal [1] or Haemophilus influenzae type b meningitis [2], for some diseases, such as influenza, we know this is not true as the disease burden varies year to year and can soar to very high levels during a pandemic [3]. Some pathogens such as the meningococcus can form a hybrid of these two paradigms having both a baseline endemic rate of disease that can be augmented, sometimes quite dramatically, by outbreaks of disease. In this review, we wish to discuss meningococcal outbreaks with an emphasis on meningococcus serogroup B and it’s capacity to cause both small and large outbreaks of disease as well as the historical and current role of vaccines in the prevention and management of such outbreaks. To do this, we will review the extent and duration of selected recent meningococcal B outbreaks with an emphasis on outbreaks where vaccine interventions have been used to control
∗ Corresponding author. Tel.: +1 5138030747. E-mail address: [email protected] (S. Black). http://dx.doi.org/10.1016/j.vaccine.2015.06.046 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
the outbreak. This is timely in view of the recent use of one investigational meningococcal B vaccine in two US college outbreaks and the recent licensure of this vaccine and one additional meningococcal B vaccine which target broad protection against meningococcal B disease. Before considering these factors, it is useful to review definitions of endemic and epidemic disease or outbreaks as well as the baseline epidemiology of the meningococcus. Endemic cases comprise the normal “background rate” of disease. Such cases tend to be sporadic – not to occur in geographic or temporal clusters and usually the source or index case for a new case cannot be identified. By contrast, epidemic meningococcal disease or an outbreak of disease is said to occur when cases occur in clusters geographically and in time, and are usually due to the same clone of the organism. In an outbreak, the rate of disease is higher than would otherwise be expected in the population over a given time period. Importantly, an outbreak may impact a relatively small and localized population or may affect millions of people over a wide area. Two linked cases of a very rare disease may be enough to define an outbreak. The term outbreak may also refer to an epidemic but the latter is usually said to occur when there are cases in an entire region or country [4]. While some diseases such as influenza tend to occur in epidemics and others tend to be endemic, the meningococcal
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Fig. 1. Global Meningococcal Serogroup Distribution. 1 National Advisory Committee on Immunization (NACI). Can Commun Dis Rep. 2013;36(ACS-1):1–40. 2 Centers for Disease Control and Prevention (CDC). Active bacterial core surveillance report, emerging infections program network, Neisseria meningitidis, 2012. Centers for Disease Control and Prevention (CDC) website. http://www.cdc.gov/abcs/reports-findings/survreports/mening12.pdf. 3 Neisseria meningitidis (aislaminetos invasores). Instituto Nacional de la Salud. Grupo de Microbiologia. Dec 2012. 4 Informe Regional de SIREVA II, 2012. Washington, DC: Organización Panamericana de la Salud; 2013. 5 European Centre for Disease Prevention and Control (ECDC). Surveillance of Invasive Bacterial Diseases in Europe, 2011. Stockholm, Sweden: ECDC; 2013. 6 Ceyhan M, et al. Poster presented at: 31st Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID); May 28–June 1, 2013; Milan, Italy. 7 Al-Mazrou YY, et al. Saudi Med J. 2004;25:1410–1413. 8 Intercountry Support Team – West Africa Week 49–52, 2012. World Health Organization website. Meningitis Weekly Bulletin. http://www.meningvax. org/files/BulletinMeningite2012 S49 52.pdf. 9 GERMS-SA Annual Report 2011. Group for Enteric, Respiratory and Meningeal disease Surveillance in South Africa (GERMS-SA) website. http://nicd.ac.za/?page=germs-sa&id=97. 10 Vyse A, et al. Epidemiol Infect. 2011;139:967–985. 11 Takahashi H, et al. J Med Microbiol. 2004;53:657–662. 12 Lahra MM, et al. Commun Dis Intell. 2012;36:E251-262. 13 Lopez L, et al. The Epidemiology of Meningococcal Disease in New Zealand in 2012. Institute of Environmental Science and Research Ltd (ESR); 2013.
disease can occur as an endemic phenomenon, as relatively small outbreaks or as large-scale epidemic disease. Additionally, some authors have used the term hyper-endemic to refer to prolonged outbreaks of meningococcal disease where the incidence of disease remains elevated for a prolonged period of time. Importantly, when meningococcal outbreaks occur, they have been associated with higher mortality than endemic disease [5].
2. Global epidemiology of meningococcal disease Meningococcal disease is an important public health concern globally because of the high rates of sequelae and mortality associated with infection. As of 2012, it was estimated that up to 1.2 million cases occur annually resulting in more than 100,000 deaths [6]. Recently, overall disease rates in the African meningitis belt as well as Europe and the US have fallen largely due to the use of conjugate vaccines in these areas. However, it is important to note that disease rates for meningococcal B have also fallen to historical low levels in the US without vaccine introduction [7]. Neisseria meningiditis, the causative organism of meningococcal disease, exists in multiple serogroups with serogroups A, B, C, Y, and W currently accounting for most disease globally. However, the epidemiology of this disease has varied both geographically and over time [8] (Fig. 1). Also, within a serogroup, new clones frequently emerge some of which have increased virulence and can be associated with a specific outbreak [9]. Perhaps the best example of the geographically variable nature of meningococcal disease is the distinct epidemiology of the disease in the so called “African meningitis belt” as compared to other areas of the world. This geographic area stretching across sub-Saharan Africa from Senegal to Ethiopia is characterized by usually annual epidemics of meningococcal disease which may be associated with incidences as high as
1000 per 100,000 person-years or more than 200 times higher than the incidence in other areas of the world [10,13]. However, recently overall incidence has declined dramatically following introduction of a monovalent meningococcal A conjugate vaccine. [11] In the US and Europe, serogroup prevalence and incidence have also varied over time. Serogroup A was a common cause of disease in Europe and the US up until the 1950s after which it rapidly declined with the last serogroup A outbreak described in Finland in the mid-1970s [8]. In both Europe and the US, the overall incidence of meningococcal disease has waxed and waned in roughly 15–20 year cycles [12]. In the US, the incidence peaked in the 1990s with an incidence of 1.7 cases/100,000 person-years and had been declining since then [13]. Disease incidence in the US is highest in infants with a second disease peak in teenagers [10]. Disease manifestations include sepsis and meningitis. Mortality even with intensive care approaches 10% with sequelae including skin scarring, hearing loss and limb loss as well as cognitive disabilities occurring in up to 50% of cases [14]. Currently, meningococcal serogroups C and B account for the majority of disease in the US.[15] While it has been relatively straightforward to develop polysaccharide conjugate vaccine for serogroups A, C, W, and Y, this has not been possible for serogroup B due to lack of immunogenicity of such conjugates and their potential to cause autoimmune disease because of cross reactivity of serogroup B capsule with human selfantigens [16]. Thus the evolution of vaccines for serogroup B has taken longer and been more complicated.
3. Outbreaks and epidemics Although outbreaks and epidemics of meningococcal disease are often thought of as rare events, in fact they are not uncommon and have occurred in all continents over the past decade. In a 2006
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review of outbreaks of meningococcal disease in the United States, Rosenstein and co-authors identified 69 outbreaks of meningococcal disease between 1994 and 2002 in the US alone with an average of 9.5 outbreaks per year including 12 that occurred in colleges and universities and 19 that occurred in primary and secondary schools. Of note is that cases that were identified in outbreaks had a 3.3 fold higher case-fatality rate than cases outside of outbreaks implying that outbreaks were being causing by hyper-virulent strains [5]. Global data on the frequency of outbreaks is difficult to obtain. To assess the possible frequency of such outbreaks globally we utilized the HealthMap utility to assess possible meningococcal disease activity. The health map utility assigns a composite score of the degree of noteworthiness based either on the significance of the rating provided by HealthMap users or disease importance and news volume associated with the disease alert. Each marker may indicate more than one Neisseria meningitidis alert. Larger markers indicate a country-level alert while local alerts (city, state, province) are indicated by smaller markers. Colorcoding of markers (lighter to darker) reflect an informal scale to highlight newsworthiness (not validated in a formal research setting) and allow HealthMap users to focus on most interesting alerts. Data was plotted using the following search terms: Diseases = ”Meningitis – Neisseria”, Locations = ”all”, Category = ”New & Ongoing Outbreaks/Warnings/International Significance”, and Time Period = ”01/01/2010 to 04/01/2014”. HealthMap.org has been active since 2006 and the application functions by acquiring data on internet search frequency using key disease terms, characterizing the information, interpreting disease activity, and disseminating alerts using a series of automated text-processing algorithms. While this technology is new, the patterns obtained have been shown to be similar to those obtained using classical surveillance techniques for other diseases [17,18]. Fig. 2 shows heat maps illustrating imputed Neisseria meningiditis activity based upon internet queries from January 2010 to April 2014 generated from the HealthMap website [17,18]. To our knowledge, this is the first time this technique has been used to assess possible meningococcal activity and thus our use must be viewed as exploratory. However, as can be seen from the region specific HealthMap for US/Canada, South America, Australia/New Zealand, and Europe, meningococcal disease activity as reflected by this technology, although it varies in size and extent, would seem to be relatively common. Several well-documented epidemics have occurred globally in the past four decades. Some epidemics such as those in Cuba between 1976 and 1993 and in New Zealand between 1991 and 2007 involved thousands of people and lasted many years. Others were smaller and shorter. While endemic disease cases are sporadic and can result from multiple clones, most epidemics are due to the emergence of a virulent clone that becomes dominant in the epidemic area [19]. Why most of these epidemics remain relatively geographically isolated is not well understood. Importantly, meningococcal serogroup B has accounted for many of these outbreaks. Moraes and Barata reviewed the epidemiology of meningococcal disease in Sao Paulo during the 20th century. Their review illustrates both the episodic nature of epidemics as well as the dramatically increased incidence of disease that can be observed during an epidemic [20]. During the period 1900–1920 they observed a baseline incidence ranging between 0.0 and 4.4 cases/100,000 person-years. During an epidemic period between 1920 and 1924, the incidence peaked at 12.2 cases/100,000 personyears and then fell to an endemic rate ranging between 1.3 and 3.5 cases/100,000 person-years. Another epidemic in the period 1945–1951 had a peak incidence of 24.2 cases/100,000 person-years. Two overlapping epidemics occurred in the 1970s first of serogroup C with a peak incidence of 30 cases/100,000
Table 1 Overview of selected outbreaks of meningococcal B disease and associated vaccine interventions. Location
Duration (years)
Norway
1974–1990
Cuba
1975–1993
Chile
1985–1990
New Zealand Oregon
1991–2007 1994–1998 2015
Normandy
2006–
Princeton
2013–
UC Santa Barbara
2013–
Vaccine intervention Norwegian B:15:P1.7,16 MenBvac® OMV Vaccine VA-MENGOC-BC® OMV using strain B:4:P1.19,15:L3,7,9 Both Norwegian MenBvac® OMV and Cuban VA-MENGOC-BC® were considered for use, but were not immunogenic in the young children for the heterologous Chilean strain MeNZB® OMV using strain P1.7-2,4 None Bexsero® 4 component Meningococcal B vaccine and Trumenba® 2 component Meningococcal B vaccine Norwegian B:15:P1.7,16 MenBvac® OMV Vaccine Bexsero® 4 component Meningococcal B vaccine Bexsero® 4 component Meningococcal B vaccine
person-years and then with serogroup A with a peak incidence in Sao Paulo of 180 cases/100,000 person-years. During the period 1990–2002, the incidence fell to 6 cases/100,000 person-years with 59% of cases due to serogroup B and 36% caused by serogroup C. By the early years of the 21st century, approximately two-thirds of cases were serogroup C [8]. This chronology dramatically illustrates the dynamic and unpredictable nature of both sero-epidemiology and epidemic disease. To further explore the nature and impact of meningococcal B epidemics, we will consider in more detail several individual outbreaks and epidemics that are summarized in Table 1. 4. The Norwegian epidemic Meningococcal disease outbreaks in Norway account for some of the first well documented outbreaks. Evidence exists of local meningitis outbreak in Norway as early as 1969 but the precise incidence rate remains unknown [21]. Although the number of cases seemed to decline in the period of 1970–1972, the number of confirmed N. meningitidis isolates started to increase again in 1973 mostly due to serogroup A and B [22]. The highest disease rates were observed starting in 1974 in northern Norway with a recorded incidence rate of 26.3 per 100,000 population and with a peak of incidence rate in 1975 of 54.5 per 100,000 population with most cases due to serogroup B [22]. This outbreak slowly spread southwards with about 300 cases being reported annually and a case fatality rate of 4% during 1985–1993 increasing to 17% during 1994–2002 [23,24]. It is estimated that 80% of these cases were due to serogroup B with a predominant B:15:P1.7,16/cc-32 serotype [24,25]. Between 1994 and 2002 the distribution of phenotypes changed with a decrease in cases due to B:15/cc-32 and a concomitant increase of those due to C:15:P1.7,16/cc-32 and other complexes contributing to the highest case fatality rate in western Norway [24]. 4.1. Development of a vaccine In 1983 the National Institute of Public Health of Norway started the development of a vaccine against serogroup B meningococcal disease. The Norwegian meningococcal B vaccine (MenBvacTM ) was an outer membrane (OM) based product prepared from a single
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Fig. 2. HealthMap data for Neisseria meningiditis activity in North America, South America, Europe, and Australia 2000–2014.
strain isolated from a fatal case that occurred during the Norwegian epidemic containing strain B:15:P1.7,16, L.3.7, P5.C,5 as 25 g/ml of purified OMV, plus aluminum hydroxide, and thimerosal [26]. The vaccine was administered intramuscularly in school randomized, placebo controlled trial a schedule of two doses in 180,000 adolescents which demonstrated a vaccine efficacy of 87% for the initial ten-months following vaccination and 57% over 29 months of observation. [26]. In other studies, doses were given to infants and adults and the utility of a booster dose was evaluated. In these studies, MenBvacTM was safe with most adverse events related to local reactions and those being less frequent after booster doses [27].
4.2. The Cuban epidemic In 1975, a nationwide epidemic outbreak occurred across Cuba with an initial incidence of 0.4–0.8 per 100,000 population [28]. In 1979 it reached 5.6 per 100,000 population. Bacterial meningococcal serogroups C and B where identified as responsible for as much as 50% and 35% of all clinically recorded cases respectively which mainly affected children between 10 and 14 year of age, but also infants under the age of one. The only readily available vaccine at that time was the polysaccharide AC vaccine which was used to vaccinate more than 3 million people between the ages of 3 months to 19 years of age. [28,29]. However, the incidence
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of bacterial meningitis cases continued to increase and a switch to meningococcal serogroup B predominance was observed with serogroup B accounting for 78.4% of all cases. By 1984, the incidence of meningococcal disease had increased to 14.4 per 100,000 population with a high mortality rate. In infants, the most affected age group, had an incidence of 120 per 100,000 population [28,29]. 4.3. Development of a vaccine In 1983, the Cuban Ministry of health decided to develop a vaccine against serogroup B meningococcus [28]. This process took six years including development and clinical trials [30–32]. The vaccine, VA-MENGOC-BC® , was produced by the newly built Findlay Institute of Serums and Vaccines in Havana and contained purified proteins from the outer membrane of serogroup B:4:P1.19,15 strain, plus a purified capsular polysaccharide from a serogroup C meningococcus strain. This was the first MenB OMV-based vaccine produced in response to an epidemic outbreak. VA-MENGOC-BC® is a 0.5 ml injectable suspension for intramuscular use containing 50 g of OMV from serogroup B meningococcus (B:4:P1.19,15 strain) and 50 g of the purified capsular polysaccharide of meningococcal serogroup C (cc11 strain), adsorbed in aluminum hydroxide gel as adjuvant, plus other excipients [33,34]. Results from clinical trials showed that adverse effects were limited to mild fever and moderate pain at the injection site [34]. In double-blind controlled clinical trials conducted mainly in Cuba and Brazil, the vaccine only showed a trend toward effectiveness in children 24–47 months of age of 47% (95% CI −72 to 84) and had 74% (95% CI 16–92) effectiveness in children 4–6 years of age. Adolescents and adults had an efficacy of 81% (95% CI 44–93). The vaccine was less immunogenic in children less than two years of age than in older age groups [35]. The implementation of a nationwide vaccination strategy was carried out beginning in 1989. VA-MENGOC-BC® was added to the National Immunization Program with a 2-dose schedule (first dose at 3 months and the second at 5 months of age following the mass campaign. This resulted in a reduction of the incidence of meningococcus B related disease to 0.2 per 100,000 population as of December 2006 [28]. The development of this clone specific OMV meningococcal serogroup B vaccine was historic because of its widespread use and impact. However, since this vaccine was tailor made to address the outbreak by a specific clone, it is important to note that efficacy against heterologous clones has not been demonstrated. 5. The New Zealand epidemic New Zealand experienced a large outbreak of meningococcal disease by a serogroup B B:4:P1.7–2,4 strain beginning in 1991. The number of cases increased rapidly between with an estimated 86% of new cases occurring between 1990 and 2003 [36,37]. Molecular analysis of the circulating epidemic strain revealed the high stability of PorA protein with the expression of the P1.7–2,4 PorA gene as a marker of the cc-41/44 clonal complex [37]. Since it was known from studies in Chile that protection in young children was highly strain specific in that cross protection was observed for matched but not unmatched strains [38], public health authorities in New Zealand decided to use the Cuban experience as a prototype and produce a strain specific OMV vaccine for epidemic control in New Zealand [39]. The peak of notified cases occurred in 2001 with an incidence of 17.4 cases per 100,000 persons per year with a rate of disease due to the epidemic strain of about 10 cases per 100,000 persons per year. It was determined that 80% of cases occurred in persons below 20 years of age, and 50% of cases occurred in persons of less
than 5 years. There was a higher incidence in the aboriginal Maori population and children of Pacific Island descent (429 cases per 100,000 persons per year and 640 cases per 100,000 persons per year, respectively) compared to Caucasian children (57 cases per 100,000 persons/year) [40,41]. New Zealand health authorities also carried out in parallel a study of the meningococcus B carriage status in some of the most affected and high risk populations before a tailor made vaccine was introduced in 2004 and of 1115 teenagers study 123 (11%) were found carriers of any meningococcal strain and 10 (0.9%) of these teenagers carried strain P1.7–2,4 [40]. However there was no carriage study conducted after vaccine introduction. The 79.6% of cases in 1994 presented typical characteristics of meningitis alone with the remainder having septicemia alone or with meningitis. Manifestations of petechial or purpuric rash were reported in 48.6% of cases. The reported case fatality was 5.3% [42]. In response to the epidemic, New Zealand scientists decided to develop a country-tailored-vaccine. It then took 6 years (1996–2001) to formulate an acceptable product that was at the end produced under a public-private partnership between the New Zealand Ministry of Health and Chiron Vaccines (now Novartis Vaccines), with technology transfer from the Norwegian Institute of Public Health (NIPH). MeNZB® , the vaccine was specifically developed to tackle the epidemic produced by the New Zealand strain serogroup B:4:P1.7b,4. MeNZB® was then used in a mass New Zealand immunization program to children, adolescents and young adults all under the age of 20 [43]. An accelerated clinical development pathway approach was used by NIPH that enrolled health care adult volunteers in a phase I/II trial. This was followed by trials involving children aged 8–12 years, 16–24 months, 6–8 months, and 6–10 weeks. The next step involved vaccination of school children after assessment of immunogenicity and safety was ascertained. In total approximately 1500 participants enrolled in the clinical trials over 2 years. Characterization of specific antibody-mediated response was performed alongside to support to facilitate the rapid progress toward licensure [40,42]. MeNZB® was granted provisional license by the New Zealand licensing authority for persons aged 6 months to 19 years in July 2004, and subsequently for persons aged 6 weeks in February 2005. The vaccine was given to more than 1.1 million young New Zealanders after regulatory approval. MeNZB® contained 25 g of OMVs from MenB NZ98/254 strain and 1.65 g of aluminum hydroxide as adjuvant. Clinical studies using a three-dose regimen, showed that MeNZBTM was well tolerated and that induced a good serological response against the vaccine strain 4–6 weeks after the third vaccination in adults (96% CI 79–100%), children (76% CI 72–80%), toddlers (75% CI 69–80%) and infants (74% CI 67–80%) [40,44,45]. The New Zealand epidemic began to wane approximately one year after the clinical trials started and before the vaccine program commenced in contrast with previously reported serogroup B epidemics which have lasted 10–15 years and then naturally ended [45]. Following introduction of the MeNZB® vaccine, a steady reduction in observed cases was observed. Vaccine effectiveness in this outbreak has been estimated to be 73% with the risk of disease in unvaccinated individuals being 3.7 times higher than in the vaccinated cohort and by 2008 the overall rate of disease had dropped to 1.1 cases/100,000 population [46].
6. Normandy France outbreak 2006– Although the reported incidence of invasive meningococcal disease in France has generally been low, in 2003 the incidence
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of meningococcal B disease reached 2 cases/100,000 population in the Seine-Maritime district of Normandy and rose to 31.6 cases/100,000 population by 2006 [47]. In this outbreak, disease was largely due to a single clone of B:14:P1.7,16/ST-32. Because of the predominant meningococcal B strain contained the same PorA as was used in the Norwegian OMV vaccine discussed above, this vaccine was used in France. Evaluation of the immunogenicity of this vaccine against the Normandy strain revealed results that were similar to those that had been obtained against the homologous Norwegian vaccine strain. Because of a shortage of the vaccine, the highest risk group, those age 1–4 years of age, was targeted in the vaccine program. [48] A total of 16,709 of the 26,014 people deemed eligible completed the vaccination series. By the end of vaccination campaign, incidence had dropped to 5.9 cases/100,000. Disease activity persists in this area and the risk of disease is still substantially higher than other areas in France [43]. 7. Oregon outbreaks 1993–1996 and 2015 In 1993, Oregon’s incidence of serogroup B meningococcal disease began to rise with cases being due to a cc32 strain. There were 258 cases observed between 1993 and 1996 with a peak incidence of 4.5 cases/100,000 population. The disease during the peak of the epidemic was predominantly due to an cc32 (ET-5) clone and this clone continues to predominate. No vaccine intervention has been undertaken in the state wide Oregon outbreak. While the total number of cases per year has fallen, the incidence of meningococcal disease in Oregon remains hyperendemic with rates substantially higher than in the rest of the United States, but much lower than they were during the peak of the outbreak. The reason for this difference or for the localization of the outbreak to Oregon is not understood [49]. More recently, an outbreak of meningococcal B disease has occurred at the University of Oregon in 2015 with six cases and one death [50]. Since this occurred following the US licensure of two meningococcal B vaccines, the University was able to recommend immunization of students with Trumenba® vaccine in a three dose regimen [50]. 8. Recent outbreaks at Princeton and UC Santa Barbara An outbreak of serogroup B meningococcal disease due to one meningococcal B clone was identified in March 2013 affecting eight students at Princeton University, New Jersey. A related case in a student who died at another college but had attended social events at Princeton was also identified. While no vaccine was licensed in the US for meningococcal B disease at that time, the licensure of Bexsero meningococcal vaccine by the European Medical Authority (EMA) [51] in Europe provided an option for intervention. In December 2013 (nine months after the start of the outbreak), under special regulatory procedures developed for the imported vaccine, the four component meningococcal B vaccine (Bexsero® ) was used in a large scale vaccination program in undergraduate students at Princeton University with over 95% of students having received at least one dose. The vaccine became available only after the CDC filed an Investigational New Drug (IND) application with the Food and Drug Administration requesting special permission for use with more than 5000 Princeton University students. Acceptance of the vaccination program was very high with more than 90% of students having received two doses of the vaccine. There have been no new cases since the introduction of the vaccination program [51]. The University made the vaccine available to all entering freshman in the Fall of 2014. In November 2013, another serogroup B outbreak, due to an unrelated strain, was reported at the University of California at Santa Barbara where four students were infected with no deaths but
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one student had to have both his feet amputated due to the infection. This outbreak triggered a second emergency vaccine campaign under a CDC IND with Bexsero® for approximately 20,000 students at University of California at Santa Barbara [51]. Monitoring of both programs by the CDC did not reveal any safety concerns. Unfortunately, studies of immunogenicity and effectiveness were not undertaken.
9. Discussion Although relatively rare, disease due to Neisseria meningiditis has long been recognized as a significant public health problem due to the high rates of morbidity and mortality associated with invasive meningococcal disease. In reviewing recent meningococcal outbreaks, it is informative to compare the response to major long lasting outbreaks such as those that occurred in Cuba, Norway, New Zealand and Oregon with the response to relatively smaller recent outbreaks at Princeton University, the University of California Santa Barbara and the University of Oregon. In Oregon, rates of disease still remain higher than baseline US rates two decades after the epidemic and no vaccine intervention has been undertaken. In Cuba, Norway and New Zealand, while vaccines specifically tailored to the group B epidemic causing clones were eventually developed, this process took many years and the respective populations suffered significant disease burden during this time period. In Chile, consideration was given to use either the existing Norwegian or Cuban vaccines for a large epidemic, but immunologic testing revealed poor immunogenicity against the heterologous strain causing the Chilean outbreak. Therefore no vaccine intervention was undertaken and the outbreak persisted for several years. In contrast, the Norwegian OMV vaccine was used in the Normandy region of France when an outbreak due to a strain very closely related the one in the Norwegian vaccine occurred. However, vaccine coverage was limited by delays in the manufacture of this tailor made vaccine and a less than anticipated total number of doses being available. Because this vaccine had been made for one time use in Norway, limited stockpiles and manufacturing capacity existed to address the French outbreak. Currently disease rates in this area of France remain substantially higher than the rest of the country. In the US, while outbreaks are a public health issue representing less than 5% of all meningococcal disease cases [52], their high human and societal cost mandates that an intervention is employed once outbreaks are recognized or, ideally, that they be prevented from occurring in the first place. Regarding meningococcal disease outbreak intervention, one should consider the following: First, with antibiotic chemoprophylaxis, it has been shown that control of an outbreak may be achievable in smaller, closed group settings [53] but chemoprophylaxis may fail to halt outbreaks in larger groups (e.g. university setting) as was observed over three academic years in one university outbreak leading to a fatality [54]. Thus for outbreak control, chemoprophylaxis does not seem to be a viable option. Second, if one waits to treat cases as they occur, it is important to recognize that despite antibiotic treatment, 9 to 12% of patients with invasive meningococcal disease will die and up to half of survivors will have long term sequelae [52]. Finally, because an optimal protective immune response to vaccination requires two doses of Bexsero® and three doses of Trumenba® given 4–6 weeks apart and because antibody responses lag 7–14 doses after each dose, campaigns to immunize urgently during outbreak situations have inherent limitations in quickly interrupting rapid disease transmission between close contacts and preventing disease. These inherent delays result in morbidity and mortality as has been seen in the Princeton and UC Santa Barbara and other outbreaks. This risk of secondary spread of a virulent clone outside the initial
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population is something that cannot be addressed by limited outbreak vaccine programs. Of note is that while serogroup C was commonly associated with university outbreaks prior to 2005, that with increased vaccine coverage with quadravalent meningococcal conjugate vaccine (MenACWY), even in the absence of a change in incidence, the proportion of disease on college campuses due to serogroup B will likely increase [54]. This pattern has been observed in Europe where 90% of cases are now caused by serogroup B following the routine use of vaccines against serogroup C meningococci [55]. The US is now facing a paradigm shift prompted by the precedent-setting event in Princeton where the only available vaccine protective against serogroup B (and not licensed in the US) was administered to more than 5000 US students. In the case of both the Princeton and UC Santa Barbara outbreaks, the time between identification of the outbreak and intervention was reduced from years to several months. Because the Bexsero® vaccine had been licensed in Europe, the FDA and CDC were willing and able to use this vaccine in large vaccination programs at the two universities albeit as an investigational agent. Currently, both the Pfizer Trumenba® and Novartis Bexsero® are FDA approved and deliberations regarding recommendations for their use are underway at the ACIP. Both vaccines have demonstrated immunogenicity in adolescents following two doses of Bexsero® and three doses of Trumenba® . Only the Bexsero brand vaccine has been shown to be safe and immunogenic in infants. Although questions remain regarding the breadth of the strain coverage of the two vaccines and the extent of indirect protection provided by these vaccines, they offer for the first time the potential to broadly prevent meningococcal B disease. However, while licensure of meningococcal B vaccines in the US obviates the need for IND use, lack of a routine use recommendation for risk groups such as the military, adolescents and college students would save the cost of vaccinating these groups but leave us in a situation that still requires expenditure of significant public health resources to identify and manage vaccination campaigns for outbreaks. In addition, by definition, designation of an outbreak requires that a significant number of cases be identified with resultant morbidity and risk of mortality in those cases. One could argue that, for these groups, consideration should be given to routine vaccination against meningococcal B infection, as is now done routinely for other meningococcal serogroups.
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Some agent characteristics and their coexistence related to occurrence and severity of systemic meningococcal disease in Norway, Winter 1981–1982. NIPH Ann 1983;6(1):75–84. Smith I, Caugant DA, Hoiby EA, Wentzel-Larsen T, Halstensen A. High casefatality rates of meningococcal disease in Western Norway caused by serogroup C strains belonging to both sequence type (ST)-32 and ST-11 complexes, 1985–2002. Epidemiol Infect 2006;134(6):1195–202. Smith I, Bjornevik AT, Augland IM, Berstad A, Wentzel-Larsen T, Halstensen A. Variations in case fatality and fatality risk factors of meningococcal disease in Western Norway, 1985–2002. Epidemiol Infect 2006;134(1):103–10. Bjune G, Hoiby EA, Gronnesby JK, Arnesen O, Holst Fredriksen J, Lindbak AK, et al. Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 1991;338(8775):1093–6. Nokleby H, Aavitsland P, O’Hallahan J, Feiring B, Tilman S, Oster P. Safety review: two outer membrane vesicle (OMV) vaccines against systemic Neisseria meningitidis serogroup B disease. Vaccine 2007;25(16):3080–4. Sotolongo F, Campa C, Casanueva V, Fajardo EM, Cuevas IE, Gonzalez N. Cuban meningococcal BC vaccine: experiences & contributions from 20 years of application. MEDICC Rev 2007;9(1):16–22. Boutriau D, Poolman J, Borrow R, Findlow J, Diez-Domingo J, Puig-Barbera J, et al. Immunogenicity and safety of three doses of a bivalent (B:4:p1.19,15 and B:4:p1.7-2,4) meningococcal outer membrane vesicle vaccine in healthy adolescents. Clin Vaccine Immunol 2007;14(1):65–73. Rico Cordeiro O, Jimenez Barreras R, Pereira Colls C. Meningococcal disease and VA-MENGOC BC in minors less than 1 year of age. Cuba, 1983 to 1991. Rev Cubana Med Trop 1996;48(1):34–9. Rico Cordeiro O, Pereira Colls C, Fernandez AA. The post-licensing efficacy of VAMENGOC-BC in children under 6 in Holguin, Cuba. The first year of observation. Rev Cubana Med Trop 1995;47(1):59–64. Rico Cordeiro O, Bravo Gonzalez JR, Diaz Gonzalez M. Effectiveness of VAMENGOC-BC in children from 0 to 5 years of age in Cuba First year of observation. Rev Cubana Med Trop 1994;46(2):94–8. Gorringe AR, Pajon R. Bexsero: a multicomponent vaccine for prevention of meningococcal disease. Hum Vaccines Immunother 2012;8(2):174–83. Devoe IW, Gilchrist JE. Release of endotoxin in the form of cell wall blebs during in vitro growth of Neisseria meningitidis. J Exp Med 1973;138(5):1156–67. Fredriksen HJ, Rosenqvist E, Wedege E, Holst J. Production, characterization and control of MenB-vaccine “Folkehelsa”: an outer membrane vesicle vaccine against group B meningococcal disease. NIPH Ann 1991;14:67–79, discussion 79-80. Martin DR, Walker SJ, Baker MG, Lennon DR. New Zealand epidemic of meningococcal disease identified by a strain with phenotype B:4:P1.4. J Infect Dis 1998;177(2):497–500. Dyet KH, Martin DR. Clonal analysis of the serogroup B meningococci causing New Zealand’s epidemic. Epidemiol Infect 2006;134(2):377–83. Tappero JW, Lagos R, Ballesteros AM, Plikaytis B, Williams D, Dykes J, et al. Immunogenicity of 2 serogroup B outer-membrane protein meningococcal vaccines: a randomized controlled trial in Chile. JAMA 1999;281(16): 1520–7. Holst J, Oster P, Arnold R, Tatley M, Næss L, Aaberge I, et al. Vaccines against meningococcal serogroup B disease containing outer membrane vesicles (OMV): lessons from past programs and implications for the future. Hum Vaccines Immunother 2013;9(6):1241–53. Jackson C, Lennon DR, Sotutu VT, Yan J, Stewart JM, Reid S, et al. Phase II meningococcal B vesicle vaccine trial in New Zealand infants. Arch Dis Child 2009;94(10):745–51.
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Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
Prevention and control of meningococcal outbreaks: The emerging role of serogroup B meningococcal vaccines Ernesto Oviedo-Orta a , Sohail Ahmed a , Rino Rappuoli a , Steven Black b,∗ a b
Novartis Vaccines, Siena, Italy Center for Global Health Cincinnati Children’s Hospital, 3333 Burnett Avenue, Cincinnati, OH 45229, USA
a r t i c l e
i n f o
Article history: Received 18 March 2015 Received in revised form 3 June 2015 Accepted 5 June 2015 Available online 17 June 2015 Keywords: Outbreak Meningococcal disease Meningococcal B disease Meningococcal B vaccines
a b s t r a c t Recently an investigational meningococcal B vaccine has been used in two college outbreaks in the US. This is the first time that a meningococcal B vaccine has been used for outbreak control in the US. However, strain specific vaccines for meningococcal B outbreaks have been developed in Norway, Cuba and to control a large prolonged outbreak in New Zealand. Although meningococcal disease is mostly endemic and baseline rates in the US have fallen over the past decade, outbreaks are not uncommon in the US and globally. In an outbreak, disease risk can rise 1000 fold or more and such outbreaks can last a decade or longer causing significant morbidity and mortality. Here we review the evolution of several serogroup B outbreaks, and, when applicable, the development and impact of meningococcal B vaccines to control these outbreaks. Prior to the availability of “broad spectrum” meningococcal B vaccines, vaccines developed to control meningococcal B outbreaks were strain specific. With the development of two newly licensed meningococcal B vaccines – a four component meningococcal B vaccine (Bexsero® , Novartis) and the two component fHBP vaccine (Trumenba® , Pfizer) that target a broad array of meningococcal B strains, there is now the potential to prevent outbreaks and as well as to shorten the delay between identification of an outbreak and availability of a vaccine. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction The epidemiology of a disease is often described as if the incidence and disease burden were both a steady state with age specific incidences being described. While this is largely true for diseases such as pneumococcal [1] or Haemophilus influenzae type b meningitis [2], for some diseases, such as influenza, we know this is not true as the disease burden varies year to year and can soar to very high levels during a pandemic [3]. Some pathogens such as the meningococcus can form a hybrid of these two paradigms having both a baseline endemic rate of disease that can be augmented, sometimes quite dramatically, by outbreaks of disease. In this review, we wish to discuss meningococcal outbreaks with an emphasis on meningococcus serogroup B and it’s capacity to cause both small and large outbreaks of disease as well as the historical and current role of vaccines in the prevention and management of such outbreaks. To do this, we will review the extent and duration of selected recent meningococcal B outbreaks with an emphasis on outbreaks where vaccine interventions have been used to control
∗ Corresponding author. Tel.: +1 5138030747. E-mail address: [email protected] (S. Black). http://dx.doi.org/10.1016/j.vaccine.2015.06.046 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
the outbreak. This is timely in view of the recent use of one investigational meningococcal B vaccine in two US college outbreaks and the recent licensure of this vaccine and one additional meningococcal B vaccine which target broad protection against meningococcal B disease. Before considering these factors, it is useful to review definitions of endemic and epidemic disease or outbreaks as well as the baseline epidemiology of the meningococcus. Endemic cases comprise the normal “background rate” of disease. Such cases tend to be sporadic – not to occur in geographic or temporal clusters and usually the source or index case for a new case cannot be identified. By contrast, epidemic meningococcal disease or an outbreak of disease is said to occur when cases occur in clusters geographically and in time, and are usually due to the same clone of the organism. In an outbreak, the rate of disease is higher than would otherwise be expected in the population over a given time period. Importantly, an outbreak may impact a relatively small and localized population or may affect millions of people over a wide area. Two linked cases of a very rare disease may be enough to define an outbreak. The term outbreak may also refer to an epidemic but the latter is usually said to occur when there are cases in an entire region or country [4]. While some diseases such as influenza tend to occur in epidemics and others tend to be endemic, the meningococcal
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Fig. 1. Global Meningococcal Serogroup Distribution. 1 National Advisory Committee on Immunization (NACI). Can Commun Dis Rep. 2013;36(ACS-1):1–40. 2 Centers for Disease Control and Prevention (CDC). Active bacterial core surveillance report, emerging infections program network, Neisseria meningitidis, 2012. Centers for Disease Control and Prevention (CDC) website. http://www.cdc.gov/abcs/reports-findings/survreports/mening12.pdf. 3 Neisseria meningitidis (aislaminetos invasores). Instituto Nacional de la Salud. Grupo de Microbiologia. Dec 2012. 4 Informe Regional de SIREVA II, 2012. Washington, DC: Organización Panamericana de la Salud; 2013. 5 European Centre for Disease Prevention and Control (ECDC). Surveillance of Invasive Bacterial Diseases in Europe, 2011. Stockholm, Sweden: ECDC; 2013. 6 Ceyhan M, et al. Poster presented at: 31st Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID); May 28–June 1, 2013; Milan, Italy. 7 Al-Mazrou YY, et al. Saudi Med J. 2004;25:1410–1413. 8 Intercountry Support Team – West Africa Week 49–52, 2012. World Health Organization website. Meningitis Weekly Bulletin. http://www.meningvax. org/files/BulletinMeningite2012 S49 52.pdf. 9 GERMS-SA Annual Report 2011. Group for Enteric, Respiratory and Meningeal disease Surveillance in South Africa (GERMS-SA) website. http://nicd.ac.za/?page=germs-sa&id=97. 10 Vyse A, et al. Epidemiol Infect. 2011;139:967–985. 11 Takahashi H, et al. J Med Microbiol. 2004;53:657–662. 12 Lahra MM, et al. Commun Dis Intell. 2012;36:E251-262. 13 Lopez L, et al. The Epidemiology of Meningococcal Disease in New Zealand in 2012. Institute of Environmental Science and Research Ltd (ESR); 2013.
disease can occur as an endemic phenomenon, as relatively small outbreaks or as large-scale epidemic disease. Additionally, some authors have used the term hyper-endemic to refer to prolonged outbreaks of meningococcal disease where the incidence of disease remains elevated for a prolonged period of time. Importantly, when meningococcal outbreaks occur, they have been associated with higher mortality than endemic disease [5].
2. Global epidemiology of meningococcal disease Meningococcal disease is an important public health concern globally because of the high rates of sequelae and mortality associated with infection. As of 2012, it was estimated that up to 1.2 million cases occur annually resulting in more than 100,000 deaths [6]. Recently, overall disease rates in the African meningitis belt as well as Europe and the US have fallen largely due to the use of conjugate vaccines in these areas. However, it is important to note that disease rates for meningococcal B have also fallen to historical low levels in the US without vaccine introduction [7]. Neisseria meningiditis, the causative organism of meningococcal disease, exists in multiple serogroups with serogroups A, B, C, Y, and W currently accounting for most disease globally. However, the epidemiology of this disease has varied both geographically and over time [8] (Fig. 1). Also, within a serogroup, new clones frequently emerge some of which have increased virulence and can be associated with a specific outbreak [9]. Perhaps the best example of the geographically variable nature of meningococcal disease is the distinct epidemiology of the disease in the so called “African meningitis belt” as compared to other areas of the world. This geographic area stretching across sub-Saharan Africa from Senegal to Ethiopia is characterized by usually annual epidemics of meningococcal disease which may be associated with incidences as high as
1000 per 100,000 person-years or more than 200 times higher than the incidence in other areas of the world [10,13]. However, recently overall incidence has declined dramatically following introduction of a monovalent meningococcal A conjugate vaccine. [11] In the US and Europe, serogroup prevalence and incidence have also varied over time. Serogroup A was a common cause of disease in Europe and the US up until the 1950s after which it rapidly declined with the last serogroup A outbreak described in Finland in the mid-1970s [8]. In both Europe and the US, the overall incidence of meningococcal disease has waxed and waned in roughly 15–20 year cycles [12]. In the US, the incidence peaked in the 1990s with an incidence of 1.7 cases/100,000 person-years and had been declining since then [13]. Disease incidence in the US is highest in infants with a second disease peak in teenagers [10]. Disease manifestations include sepsis and meningitis. Mortality even with intensive care approaches 10% with sequelae including skin scarring, hearing loss and limb loss as well as cognitive disabilities occurring in up to 50% of cases [14]. Currently, meningococcal serogroups C and B account for the majority of disease in the US.[15] While it has been relatively straightforward to develop polysaccharide conjugate vaccine for serogroups A, C, W, and Y, this has not been possible for serogroup B due to lack of immunogenicity of such conjugates and their potential to cause autoimmune disease because of cross reactivity of serogroup B capsule with human selfantigens [16]. Thus the evolution of vaccines for serogroup B has taken longer and been more complicated.
3. Outbreaks and epidemics Although outbreaks and epidemics of meningococcal disease are often thought of as rare events, in fact they are not uncommon and have occurred in all continents over the past decade. In a 2006
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review of outbreaks of meningococcal disease in the United States, Rosenstein and co-authors identified 69 outbreaks of meningococcal disease between 1994 and 2002 in the US alone with an average of 9.5 outbreaks per year including 12 that occurred in colleges and universities and 19 that occurred in primary and secondary schools. Of note is that cases that were identified in outbreaks had a 3.3 fold higher case-fatality rate than cases outside of outbreaks implying that outbreaks were being causing by hyper-virulent strains [5]. Global data on the frequency of outbreaks is difficult to obtain. To assess the possible frequency of such outbreaks globally we utilized the HealthMap utility to assess possible meningococcal disease activity. The health map utility assigns a composite score of the degree of noteworthiness based either on the significance of the rating provided by HealthMap users or disease importance and news volume associated with the disease alert. Each marker may indicate more than one Neisseria meningitidis alert. Larger markers indicate a country-level alert while local alerts (city, state, province) are indicated by smaller markers. Colorcoding of markers (lighter to darker) reflect an informal scale to highlight newsworthiness (not validated in a formal research setting) and allow HealthMap users to focus on most interesting alerts. Data was plotted using the following search terms: Diseases = ”Meningitis – Neisseria”, Locations = ”all”, Category = ”New & Ongoing Outbreaks/Warnings/International Significance”, and Time Period = ”01/01/2010 to 04/01/2014”. HealthMap.org has been active since 2006 and the application functions by acquiring data on internet search frequency using key disease terms, characterizing the information, interpreting disease activity, and disseminating alerts using a series of automated text-processing algorithms. While this technology is new, the patterns obtained have been shown to be similar to those obtained using classical surveillance techniques for other diseases [17,18]. Fig. 2 shows heat maps illustrating imputed Neisseria meningiditis activity based upon internet queries from January 2010 to April 2014 generated from the HealthMap website [17,18]. To our knowledge, this is the first time this technique has been used to assess possible meningococcal activity and thus our use must be viewed as exploratory. However, as can be seen from the region specific HealthMap for US/Canada, South America, Australia/New Zealand, and Europe, meningococcal disease activity as reflected by this technology, although it varies in size and extent, would seem to be relatively common. Several well-documented epidemics have occurred globally in the past four decades. Some epidemics such as those in Cuba between 1976 and 1993 and in New Zealand between 1991 and 2007 involved thousands of people and lasted many years. Others were smaller and shorter. While endemic disease cases are sporadic and can result from multiple clones, most epidemics are due to the emergence of a virulent clone that becomes dominant in the epidemic area [19]. Why most of these epidemics remain relatively geographically isolated is not well understood. Importantly, meningococcal serogroup B has accounted for many of these outbreaks. Moraes and Barata reviewed the epidemiology of meningococcal disease in Sao Paulo during the 20th century. Their review illustrates both the episodic nature of epidemics as well as the dramatically increased incidence of disease that can be observed during an epidemic [20]. During the period 1900–1920 they observed a baseline incidence ranging between 0.0 and 4.4 cases/100,000 person-years. During an epidemic period between 1920 and 1924, the incidence peaked at 12.2 cases/100,000 personyears and then fell to an endemic rate ranging between 1.3 and 3.5 cases/100,000 person-years. Another epidemic in the period 1945–1951 had a peak incidence of 24.2 cases/100,000 person-years. Two overlapping epidemics occurred in the 1970s first of serogroup C with a peak incidence of 30 cases/100,000
Table 1 Overview of selected outbreaks of meningococcal B disease and associated vaccine interventions. Location
Duration (years)
Norway
1974–1990
Cuba
1975–1993
Chile
1985–1990
New Zealand Oregon
1991–2007 1994–1998 2015
Normandy
2006–
Princeton
2013–
UC Santa Barbara
2013–
Vaccine intervention Norwegian B:15:P1.7,16 MenBvac® OMV Vaccine VA-MENGOC-BC® OMV using strain B:4:P1.19,15:L3,7,9 Both Norwegian MenBvac® OMV and Cuban VA-MENGOC-BC® were considered for use, but were not immunogenic in the young children for the heterologous Chilean strain MeNZB® OMV using strain P1.7-2,4 None Bexsero® 4 component Meningococcal B vaccine and Trumenba® 2 component Meningococcal B vaccine Norwegian B:15:P1.7,16 MenBvac® OMV Vaccine Bexsero® 4 component Meningococcal B vaccine Bexsero® 4 component Meningococcal B vaccine
person-years and then with serogroup A with a peak incidence in Sao Paulo of 180 cases/100,000 person-years. During the period 1990–2002, the incidence fell to 6 cases/100,000 person-years with 59% of cases due to serogroup B and 36% caused by serogroup C. By the early years of the 21st century, approximately two-thirds of cases were serogroup C [8]. This chronology dramatically illustrates the dynamic and unpredictable nature of both sero-epidemiology and epidemic disease. To further explore the nature and impact of meningococcal B epidemics, we will consider in more detail several individual outbreaks and epidemics that are summarized in Table 1. 4. The Norwegian epidemic Meningococcal disease outbreaks in Norway account for some of the first well documented outbreaks. Evidence exists of local meningitis outbreak in Norway as early as 1969 but the precise incidence rate remains unknown [21]. Although the number of cases seemed to decline in the period of 1970–1972, the number of confirmed N. meningitidis isolates started to increase again in 1973 mostly due to serogroup A and B [22]. The highest disease rates were observed starting in 1974 in northern Norway with a recorded incidence rate of 26.3 per 100,000 population and with a peak of incidence rate in 1975 of 54.5 per 100,000 population with most cases due to serogroup B [22]. This outbreak slowly spread southwards with about 300 cases being reported annually and a case fatality rate of 4% during 1985–1993 increasing to 17% during 1994–2002 [23,24]. It is estimated that 80% of these cases were due to serogroup B with a predominant B:15:P1.7,16/cc-32 serotype [24,25]. Between 1994 and 2002 the distribution of phenotypes changed with a decrease in cases due to B:15/cc-32 and a concomitant increase of those due to C:15:P1.7,16/cc-32 and other complexes contributing to the highest case fatality rate in western Norway [24]. 4.1. Development of a vaccine In 1983 the National Institute of Public Health of Norway started the development of a vaccine against serogroup B meningococcal disease. The Norwegian meningococcal B vaccine (MenBvacTM ) was an outer membrane (OM) based product prepared from a single
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Fig. 2. HealthMap data for Neisseria meningiditis activity in North America, South America, Europe, and Australia 2000–2014.
strain isolated from a fatal case that occurred during the Norwegian epidemic containing strain B:15:P1.7,16, L.3.7, P5.C,5 as 25 g/ml of purified OMV, plus aluminum hydroxide, and thimerosal [26]. The vaccine was administered intramuscularly in school randomized, placebo controlled trial a schedule of two doses in 180,000 adolescents which demonstrated a vaccine efficacy of 87% for the initial ten-months following vaccination and 57% over 29 months of observation. [26]. In other studies, doses were given to infants and adults and the utility of a booster dose was evaluated. In these studies, MenBvacTM was safe with most adverse events related to local reactions and those being less frequent after booster doses [27].
4.2. The Cuban epidemic In 1975, a nationwide epidemic outbreak occurred across Cuba with an initial incidence of 0.4–0.8 per 100,000 population [28]. In 1979 it reached 5.6 per 100,000 population. Bacterial meningococcal serogroups C and B where identified as responsible for as much as 50% and 35% of all clinically recorded cases respectively which mainly affected children between 10 and 14 year of age, but also infants under the age of one. The only readily available vaccine at that time was the polysaccharide AC vaccine which was used to vaccinate more than 3 million people between the ages of 3 months to 19 years of age. [28,29]. However, the incidence
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of bacterial meningitis cases continued to increase and a switch to meningococcal serogroup B predominance was observed with serogroup B accounting for 78.4% of all cases. By 1984, the incidence of meningococcal disease had increased to 14.4 per 100,000 population with a high mortality rate. In infants, the most affected age group, had an incidence of 120 per 100,000 population [28,29]. 4.3. Development of a vaccine In 1983, the Cuban Ministry of health decided to develop a vaccine against serogroup B meningococcus [28]. This process took six years including development and clinical trials [30–32]. The vaccine, VA-MENGOC-BC® , was produced by the newly built Findlay Institute of Serums and Vaccines in Havana and contained purified proteins from the outer membrane of serogroup B:4:P1.19,15 strain, plus a purified capsular polysaccharide from a serogroup C meningococcus strain. This was the first MenB OMV-based vaccine produced in response to an epidemic outbreak. VA-MENGOC-BC® is a 0.5 ml injectable suspension for intramuscular use containing 50 g of OMV from serogroup B meningococcus (B:4:P1.19,15 strain) and 50 g of the purified capsular polysaccharide of meningococcal serogroup C (cc11 strain), adsorbed in aluminum hydroxide gel as adjuvant, plus other excipients [33,34]. Results from clinical trials showed that adverse effects were limited to mild fever and moderate pain at the injection site [34]. In double-blind controlled clinical trials conducted mainly in Cuba and Brazil, the vaccine only showed a trend toward effectiveness in children 24–47 months of age of 47% (95% CI −72 to 84) and had 74% (95% CI 16–92) effectiveness in children 4–6 years of age. Adolescents and adults had an efficacy of 81% (95% CI 44–93). The vaccine was less immunogenic in children less than two years of age than in older age groups [35]. The implementation of a nationwide vaccination strategy was carried out beginning in 1989. VA-MENGOC-BC® was added to the National Immunization Program with a 2-dose schedule (first dose at 3 months and the second at 5 months of age following the mass campaign. This resulted in a reduction of the incidence of meningococcus B related disease to 0.2 per 100,000 population as of December 2006 [28]. The development of this clone specific OMV meningococcal serogroup B vaccine was historic because of its widespread use and impact. However, since this vaccine was tailor made to address the outbreak by a specific clone, it is important to note that efficacy against heterologous clones has not been demonstrated. 5. The New Zealand epidemic New Zealand experienced a large outbreak of meningococcal disease by a serogroup B B:4:P1.7–2,4 strain beginning in 1991. The number of cases increased rapidly between with an estimated 86% of new cases occurring between 1990 and 2003 [36,37]. Molecular analysis of the circulating epidemic strain revealed the high stability of PorA protein with the expression of the P1.7–2,4 PorA gene as a marker of the cc-41/44 clonal complex [37]. Since it was known from studies in Chile that protection in young children was highly strain specific in that cross protection was observed for matched but not unmatched strains [38], public health authorities in New Zealand decided to use the Cuban experience as a prototype and produce a strain specific OMV vaccine for epidemic control in New Zealand [39]. The peak of notified cases occurred in 2001 with an incidence of 17.4 cases per 100,000 persons per year with a rate of disease due to the epidemic strain of about 10 cases per 100,000 persons per year. It was determined that 80% of cases occurred in persons below 20 years of age, and 50% of cases occurred in persons of less
than 5 years. There was a higher incidence in the aboriginal Maori population and children of Pacific Island descent (429 cases per 100,000 persons per year and 640 cases per 100,000 persons per year, respectively) compared to Caucasian children (57 cases per 100,000 persons/year) [40,41]. New Zealand health authorities also carried out in parallel a study of the meningococcus B carriage status in some of the most affected and high risk populations before a tailor made vaccine was introduced in 2004 and of 1115 teenagers study 123 (11%) were found carriers of any meningococcal strain and 10 (0.9%) of these teenagers carried strain P1.7–2,4 [40]. However there was no carriage study conducted after vaccine introduction. The 79.6% of cases in 1994 presented typical characteristics of meningitis alone with the remainder having septicemia alone or with meningitis. Manifestations of petechial or purpuric rash were reported in 48.6% of cases. The reported case fatality was 5.3% [42]. In response to the epidemic, New Zealand scientists decided to develop a country-tailored-vaccine. It then took 6 years (1996–2001) to formulate an acceptable product that was at the end produced under a public-private partnership between the New Zealand Ministry of Health and Chiron Vaccines (now Novartis Vaccines), with technology transfer from the Norwegian Institute of Public Health (NIPH). MeNZB® , the vaccine was specifically developed to tackle the epidemic produced by the New Zealand strain serogroup B:4:P1.7b,4. MeNZB® was then used in a mass New Zealand immunization program to children, adolescents and young adults all under the age of 20 [43]. An accelerated clinical development pathway approach was used by NIPH that enrolled health care adult volunteers in a phase I/II trial. This was followed by trials involving children aged 8–12 years, 16–24 months, 6–8 months, and 6–10 weeks. The next step involved vaccination of school children after assessment of immunogenicity and safety was ascertained. In total approximately 1500 participants enrolled in the clinical trials over 2 years. Characterization of specific antibody-mediated response was performed alongside to support to facilitate the rapid progress toward licensure [40,42]. MeNZB® was granted provisional license by the New Zealand licensing authority for persons aged 6 months to 19 years in July 2004, and subsequently for persons aged 6 weeks in February 2005. The vaccine was given to more than 1.1 million young New Zealanders after regulatory approval. MeNZB® contained 25 g of OMVs from MenB NZ98/254 strain and 1.65 g of aluminum hydroxide as adjuvant. Clinical studies using a three-dose regimen, showed that MeNZBTM was well tolerated and that induced a good serological response against the vaccine strain 4–6 weeks after the third vaccination in adults (96% CI 79–100%), children (76% CI 72–80%), toddlers (75% CI 69–80%) and infants (74% CI 67–80%) [40,44,45]. The New Zealand epidemic began to wane approximately one year after the clinical trials started and before the vaccine program commenced in contrast with previously reported serogroup B epidemics which have lasted 10–15 years and then naturally ended [45]. Following introduction of the MeNZB® vaccine, a steady reduction in observed cases was observed. Vaccine effectiveness in this outbreak has been estimated to be 73% with the risk of disease in unvaccinated individuals being 3.7 times higher than in the vaccinated cohort and by 2008 the overall rate of disease had dropped to 1.1 cases/100,000 population [46].
6. Normandy France outbreak 2006– Although the reported incidence of invasive meningococcal disease in France has generally been low, in 2003 the incidence
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of meningococcal B disease reached 2 cases/100,000 population in the Seine-Maritime district of Normandy and rose to 31.6 cases/100,000 population by 2006 [47]. In this outbreak, disease was largely due to a single clone of B:14:P1.7,16/ST-32. Because of the predominant meningococcal B strain contained the same PorA as was used in the Norwegian OMV vaccine discussed above, this vaccine was used in France. Evaluation of the immunogenicity of this vaccine against the Normandy strain revealed results that were similar to those that had been obtained against the homologous Norwegian vaccine strain. Because of a shortage of the vaccine, the highest risk group, those age 1–4 years of age, was targeted in the vaccine program. [48] A total of 16,709 of the 26,014 people deemed eligible completed the vaccination series. By the end of vaccination campaign, incidence had dropped to 5.9 cases/100,000. Disease activity persists in this area and the risk of disease is still substantially higher than other areas in France [43]. 7. Oregon outbreaks 1993–1996 and 2015 In 1993, Oregon’s incidence of serogroup B meningococcal disease began to rise with cases being due to a cc32 strain. There were 258 cases observed between 1993 and 1996 with a peak incidence of 4.5 cases/100,000 population. The disease during the peak of the epidemic was predominantly due to an cc32 (ET-5) clone and this clone continues to predominate. No vaccine intervention has been undertaken in the state wide Oregon outbreak. While the total number of cases per year has fallen, the incidence of meningococcal disease in Oregon remains hyperendemic with rates substantially higher than in the rest of the United States, but much lower than they were during the peak of the outbreak. The reason for this difference or for the localization of the outbreak to Oregon is not understood [49]. More recently, an outbreak of meningococcal B disease has occurred at the University of Oregon in 2015 with six cases and one death [50]. Since this occurred following the US licensure of two meningococcal B vaccines, the University was able to recommend immunization of students with Trumenba® vaccine in a three dose regimen [50]. 8. Recent outbreaks at Princeton and UC Santa Barbara An outbreak of serogroup B meningococcal disease due to one meningococcal B clone was identified in March 2013 affecting eight students at Princeton University, New Jersey. A related case in a student who died at another college but had attended social events at Princeton was also identified. While no vaccine was licensed in the US for meningococcal B disease at that time, the licensure of Bexsero meningococcal vaccine by the European Medical Authority (EMA) [51] in Europe provided an option for intervention. In December 2013 (nine months after the start of the outbreak), under special regulatory procedures developed for the imported vaccine, the four component meningococcal B vaccine (Bexsero® ) was used in a large scale vaccination program in undergraduate students at Princeton University with over 95% of students having received at least one dose. The vaccine became available only after the CDC filed an Investigational New Drug (IND) application with the Food and Drug Administration requesting special permission for use with more than 5000 Princeton University students. Acceptance of the vaccination program was very high with more than 90% of students having received two doses of the vaccine. There have been no new cases since the introduction of the vaccination program [51]. The University made the vaccine available to all entering freshman in the Fall of 2014. In November 2013, another serogroup B outbreak, due to an unrelated strain, was reported at the University of California at Santa Barbara where four students were infected with no deaths but
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one student had to have both his feet amputated due to the infection. This outbreak triggered a second emergency vaccine campaign under a CDC IND with Bexsero® for approximately 20,000 students at University of California at Santa Barbara [51]. Monitoring of both programs by the CDC did not reveal any safety concerns. Unfortunately, studies of immunogenicity and effectiveness were not undertaken.
9. Discussion Although relatively rare, disease due to Neisseria meningiditis has long been recognized as a significant public health problem due to the high rates of morbidity and mortality associated with invasive meningococcal disease. In reviewing recent meningococcal outbreaks, it is informative to compare the response to major long lasting outbreaks such as those that occurred in Cuba, Norway, New Zealand and Oregon with the response to relatively smaller recent outbreaks at Princeton University, the University of California Santa Barbara and the University of Oregon. In Oregon, rates of disease still remain higher than baseline US rates two decades after the epidemic and no vaccine intervention has been undertaken. In Cuba, Norway and New Zealand, while vaccines specifically tailored to the group B epidemic causing clones were eventually developed, this process took many years and the respective populations suffered significant disease burden during this time period. In Chile, consideration was given to use either the existing Norwegian or Cuban vaccines for a large epidemic, but immunologic testing revealed poor immunogenicity against the heterologous strain causing the Chilean outbreak. Therefore no vaccine intervention was undertaken and the outbreak persisted for several years. In contrast, the Norwegian OMV vaccine was used in the Normandy region of France when an outbreak due to a strain very closely related the one in the Norwegian vaccine occurred. However, vaccine coverage was limited by delays in the manufacture of this tailor made vaccine and a less than anticipated total number of doses being available. Because this vaccine had been made for one time use in Norway, limited stockpiles and manufacturing capacity existed to address the French outbreak. Currently disease rates in this area of France remain substantially higher than the rest of the country. In the US, while outbreaks are a public health issue representing less than 5% of all meningococcal disease cases [52], their high human and societal cost mandates that an intervention is employed once outbreaks are recognized or, ideally, that they be prevented from occurring in the first place. Regarding meningococcal disease outbreak intervention, one should consider the following: First, with antibiotic chemoprophylaxis, it has been shown that control of an outbreak may be achievable in smaller, closed group settings [53] but chemoprophylaxis may fail to halt outbreaks in larger groups (e.g. university setting) as was observed over three academic years in one university outbreak leading to a fatality [54]. Thus for outbreak control, chemoprophylaxis does not seem to be a viable option. Second, if one waits to treat cases as they occur, it is important to recognize that despite antibiotic treatment, 9 to 12% of patients with invasive meningococcal disease will die and up to half of survivors will have long term sequelae [52]. Finally, because an optimal protective immune response to vaccination requires two doses of Bexsero® and three doses of Trumenba® given 4–6 weeks apart and because antibody responses lag 7–14 doses after each dose, campaigns to immunize urgently during outbreak situations have inherent limitations in quickly interrupting rapid disease transmission between close contacts and preventing disease. These inherent delays result in morbidity and mortality as has been seen in the Princeton and UC Santa Barbara and other outbreaks. This risk of secondary spread of a virulent clone outside the initial
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population is something that cannot be addressed by limited outbreak vaccine programs. Of note is that while serogroup C was commonly associated with university outbreaks prior to 2005, that with increased vaccine coverage with quadravalent meningococcal conjugate vaccine (MenACWY), even in the absence of a change in incidence, the proportion of disease on college campuses due to serogroup B will likely increase [54]. This pattern has been observed in Europe where 90% of cases are now caused by serogroup B following the routine use of vaccines against serogroup C meningococci [55]. The US is now facing a paradigm shift prompted by the precedent-setting event in Princeton where the only available vaccine protective against serogroup B (and not licensed in the US) was administered to more than 5000 US students. In the case of both the Princeton and UC Santa Barbara outbreaks, the time between identification of the outbreak and intervention was reduced from years to several months. Because the Bexsero® vaccine had been licensed in Europe, the FDA and CDC were willing and able to use this vaccine in large vaccination programs at the two universities albeit as an investigational agent. Currently, both the Pfizer Trumenba® and Novartis Bexsero® are FDA approved and deliberations regarding recommendations for their use are underway at the ACIP. Both vaccines have demonstrated immunogenicity in adolescents following two doses of Bexsero® and three doses of Trumenba® . Only the Bexsero brand vaccine has been shown to be safe and immunogenic in infants. Although questions remain regarding the breadth of the strain coverage of the two vaccines and the extent of indirect protection provided by these vaccines, they offer for the first time the potential to broadly prevent meningococcal B disease. However, while licensure of meningococcal B vaccines in the US obviates the need for IND use, lack of a routine use recommendation for risk groups such as the military, adolescents and college students would save the cost of vaccinating these groups but leave us in a situation that still requires expenditure of significant public health resources to identify and manage vaccination campaigns for outbreaks. In addition, by definition, designation of an outbreak requires that a significant number of cases be identified with resultant morbidity and risk of mortality in those cases. One could argue that, for these groups, consideration should be given to routine vaccination against meningococcal B infection, as is now done routinely for other meningococcal serogroups.
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