Meningococcal Vaccines: A Neglected Topic in Travel Medicine?

Abstract

Meningococcal disease is a devastating disease. Regular epidemics, particularly in the African meningitis belt and outbreaks during the Hajj pilgrimage, have caused significant morbidity and mortality. Although meningococcal vaccination is recommended for travelers to these destinations, disease awareness among travelers is generally poor. Case-fatality rates of meningococcal disease are high (10-14%) and the disease can be fatal within 24 h, even when the best healthcare is available. This is particularly relevant to travelers, as gaining timely and accurate diagnosis and treatment is often difficult in foreign countries or remote regions. Given the unpredictable epidemiology of the disease, broad meningococcal vaccination for all ages should be considered for travelers. Conjugate meningococcal vaccines have significant advantages over polysaccharide vaccines, and should be the preferred option for travelers.
Introduction

International travel and tourism continues to grow at a rapid pace. In 2008, there were 924 million international arrivals, 16 million more than in 2007.[101] Forecasts predict continued growth in international arrivals - up to 1.6 billion arrivals worldwide by 2020.[102] In 2008, the three regions that registered the biggest increases in international arrivals above their long-term average were the Middle East (11%), Africa (5%) and south and southeast Asia (4%).[101] Routine vaccinations in a traveler's home country cannot ensure protection at their destination. Thus, with increasing levels of travel to less-visited destinations, increased awareness of infectious diseases and the need for vaccination is required. There is an increased risk of acquiring diseases such as hepatitis A, Japanese encephalitis, rabies, typhoid fever and yellow fever when traveling to high-risk areas.[1] However, one disease that is often neglected in travel vaccine recommendations is meningococcal disease, despite the fact that approximately 500,000 cases of meningococcal disease and 50,000 resulting deaths occur worldwide each year.[103] The estimated incidence rate in travelers varies widely between 0.04 and 640 per 100,000, depending on destination.[2,3] This compares with 200,000 cases of yellow fever and 30,000 resulting deaths,[104] and an estimated incidence rate of 0.05-50 per 100,000 in travelers, depending on destination (Table 1).[4] However, awareness of the need for yellow fever vaccination when traveling is currently far higher than for meningococcal disease. This article aims to explore the epidemiological evidence for the risk of meningococcal disease in travelers and to re-evaluate the need for meningococcal vaccines.
Meningococcal Disease

The onset of meningococcal disease is rapid and can be fatal within 24 h, even when the best healthcare is available, and as more classic clinical symptoms occur relatively late (13-22 h), the

time window for clinical diagnosis and treatment is narrow.[5] This is particularly relevant to travelers, as gaining timely and accurate diagnosis and treatment is often difficult in foreign countries or remote regions. Even with timely and appropriate treatment, case-fatality rates are high (10-14%), and up to 20% of survivors suffer serious permanent sequelae.[6] Table 1 highlights that meningococcal disease, along with yellow fever and Japanese encephalitis, have the highest case-fatality rate of the vaccine-preventable travel-associated diseases. Meningococcal disease is predominantly caused by five different serogroups: A, B, C, W-135 and Y. Disease epidemiology is dynamic and unpredictable, varying geographically and with time. Invasive meningococcal disease incidence ranges from 0.25 to 4.4 per 100,000 individuals in European countries[105] and the USA,[106] to as high as 100-800 per 100,000 individuals during outbreaks in the 'meningitis belt' of sub-Saharan Africa (Table 2).[103] Incidence rates can also be affected by social behavior and living conditions, as any condition associated with crowding or close proximity of people is conducive to transmission. Meningococcal disease epidemiology also displays seasonal variation, which is important when traveling across hemispheres. Disease incidence has been reported to correlate with the occurrence of influenza virus, which is particularly topical in light of the recent H1N1 pandemic, especially when one considers that the symptoms of influenza may mask those of meningococcal disease. The incidence of travel-related meningococcal disease varies greatly and depends on destination, duration of travel and social behavior during travel. Table 1 shows published incidence rates for meningococcal disease in comparison with other travel-associated diseases. These data, combined with the mortality and morbidity rates, should form the basis for vaccine recommendations. Vaccine recommendations will depend on travel destinations and the purpose of travel.
Travel Destinations Africa

With an estimated total of 47 million international travelers, Africa continues to grow as a destination for tourists and those visiting friends and family.[101] The area of highest risk for meningococcal disease in Africa is the so-called African meningitis belt, where disease outbreaks occur regularly and disease incidence can be as high as 1000 per 100,000 individuals during outbreaks.[103] In 1996, this was the site of the largest recorded meningococcal disease epidemic caused by serogroup A. As many as 250,000 cases were recorded, resulting in more than 25,000 deaths in the region.[103] Epidemic waves appear to occur in cycles of 10-14 years. However, they actually vary substantially from country to country, related to a variety of factors, including the spread of new strains, the extent of previous vaccination campaigns, waning immunity, and climatic and environmental factors such as prolonged drought and dust storms.[7] Serogroup A is the predominant cause of meningococcal disease in the meningitis belt, but serogroups W-135 and X have recently emerged. The most recent data for the first 2 months of 2009 show the emergence of a serogroup A outbreak in Nigeria that has already caused 5323

suspected cases of meningococcal disease and 333 deaths.[107] Serogroup W-135 has also been identified as a cause of disease in Cameroon.[8] In 2007, a serogroup A outbreak was responsible for more than 22,000 cases and approximately 1500 deaths in Burkina Faso.[108] Previously, a serogroup W-135 outbreak caused more than 13,000 cases and more than 1400 deaths in 2002[9] and in 2006, serogroup X, previously not considered to be a major cause of disease, caused a significant outbreak in Niger.[10] Although there are only a few reports of travelers to the region who are affected by meningococcal disease, the number of reported cases is likely to rise with improved surveillance and increasing numbers of travelers. Furthermore, it is evident that this belt is not unique and in fact meningococcal disease incidence rates across Africa far exceed those routinely experienced in developed countries. Of particular note, increasing numbers of cases and outbreaks are being reported to the south of the traditional boundaries of the meningitis belt.[11] Expansion of the belt southwards towards the Great Lakes (located in eastern Africa and including countries surrounding Lake Kivu, Lake Tanganyika and Lake Victoria; Burundi, Kenya, Rwanda, Tanzania and Uganda),[7,109] in particular, will have significant consequences for travelers, as the region is an increasingly popular travel destination. In view of this shifting and unpredictable nature of outbreaks, quadrivalent vaccination against serogroups A, C, W-135 and Y is recommended by the US CDC and the WHO to all travelers to the region of the meningitis belt during the dry season (December-June),[12,110] and vaccination beyond the meningitis belt should also be considered, given the expansion.
Middle East

The number of international travelers visiting the Middle East as a tourist destination has increased dramatically. Notably, there has been a significant increase in international pilgrims attending the Hajj by more than 40% between 1996 and 2006, and in total, over 2 million now attend annually.[111] The high visitor density, cramped living conditions and other environmental risk factors combine to considerably increase the risk of meningococcal disease during the Hajj.[13] Nasopharyngeal meningococcal carriage rates can be as high as 86% in crowded areas around the holy Mosque in Mecca,[14] compared with 1-10% in the general population globally. As a result, there have been several meningococcal disease outbreaks in recent years, including an outbreak of serogroup A disease in 1997, and serogroup W-135 outbreaks in 2000 and 2001. The W-135 outbreak in 2000 caused more than 400 cases of meningococcal disease among Hajj pilgrims.[15] Furthermore, this outbreak led to an international spread of the disease via returning pilgrims. Clusters of W-135 meningococcal disease were reported in contacts in more than 16 countries worldwide following this outbreak.[13,15] Currently, quadrivalent meningococcal vaccination is a visa requirement for entry into the Kingdom of Saudi Arabia during the Hajj.[16] In the USA and Canada, quadrivalent meningococcal conjugate vaccine is recommended for travelers to the Hajj,[17] and elsewhere polysaccharide vaccine is the only available option to many of the pilgrims.

Similarly, the Umrah pilgrimage to Mecca is increasing in size and individuals may return for Umrah regularly. Although conditions are not as crowded as during the Hajj, the risk of meningococcal disease remains, and quadrivalent vaccination is also required for this visit.
Other Regions

In Asia, disease outbreaks have occurred in Mongolia (serogroup A),[18] China (serogroup C),[112] the Philippines (serogroup A),[113] India (serogroup A)[19,114] and Nepal (serogroup A).[20] Six travelers contracted meningococcal meningitis in Nepal during an outbreak in the mid-1980s, resulting in two deaths. All were adult travelers who had spent extended time with the local population while trekking.[20] In Australasia, serogroup B caused a significant outbreak in New Zealand, until a strain-specific vaccine was developed, which dramatically reduced the incidence of meningococcal disease caused by serogroup B.[8,21] In South America, major outbreaks of serogroups A, B and C have occurred in Brazil and other parts of the continent,[22-24] and an increased incidence of W-135 has recently been reported in Brazil[25] and Argentina.[26]
Air Travel

There have also been reports of meningococcal disease transmission linked to air travel. Passive surveillance in the USA disclosed 21 cases between February 1999 and May 2001: one report every 6 weeks.[27] A lethal case of meningococcal disease was reported in a 20-year-old male student travelling from Israel to the USA in 2003.[28] Furthermore, two serogroup B cases were reported on the same Los Angeles to Sydney flight,[29] and a non-Hajj-related W-135 case occurred in Singapore following travel to Morocco.[30] Finally, a case of meningococcal disease caused by serogroup A was reported in Japan following travel from China.[31] There are undoubtedly more cases of travel-related meningococcal disease that go unreported in the medical literature. Concern has led to a recent article that questioned if long-haul flights should carry antibiotics to treat acute bacterial meningitis and meningococcal disease. It concluded that there is a need for airlines to re-evaluate their response to symptoms of these conditions in terms of awareness as well as treatment.[32]
Travel for Specific Purposes

In addition to regional variation in disease incidence, living conditions and social behavior can also affect meningococcal disease transmission rates. Overcrowding, which occurs in colleges, dormitories, Hajj camps and refugee camps, can contribute to meningococcal disease transmission. For these reasons, many universities and colleges in the USA and the UK recommend vaccination against meningococcal disease (ACWY[33] and C,[115] respectively), particularly for students traveling from countries where meningococcal vaccination is not commonplace. An adolescent booster dose with quadrivalent or serogroup C vaccine has recently been recommended in Canada.[17] However, vaccine uptake is not maximal, and education and disease-awareness programs could also be beneficial in this setting.[34-36] Countries with infant meningococcal vaccination programs, such as Switzerland, are also introducing an adolescent

booster dose (serogroup C) to help maintain protection through this particularly high-risk period.[116] One further subset of the population that has also been observed to be at increased risk from meningococcal disease is military personnel.[37] Several factors contribute to this risk, such as a high-risk age group (young adults), living in close quarters and deployment to different regions at short notice. Indeed, meningococcal disease in the military spawned vaccine development against this disease; the incidence in US military trainees was so high in the 1960s that a research unit was established that was dedicated to developing an effective vaccine. Eminent work by Goldschneider, Gotschlich and Artenstein first led to a serogroup C vaccine, and later, a serogroup A vaccine.[38-42] Today, quadrivalent vaccination is recommended in the USA and many other countries for all military recruits.[43,44]
Vaccination Strategies

There are significant variations in the incidence and epidemiology of meningococcal disease, both geographically and over time.[45] Vaccination strategies therefore need to address this variation, and broad coverage against as many serogroups as possible should be offered to travelers. Until a vaccine against a range of serogroup B strains is available, the broadest coverage offered is that by quadrivalent vaccines. These vaccines can be categorized into two groups: polysaccharide and conjugate vaccines. Quadrivalent meningococcal polysaccharide vaccines (MPSV4) are safe and have an efficacy of approximately 90-95%.[11] However, polysaccharide vaccines do have limitations. The duration of protection provided by plain polysaccharide vaccines is short (3-5 years),[45] and immune hyporesponsiveness can occur after repeated vaccination,[46] which may be an issue for long-term or frequent travelers. They do not induce protective antibodies in children younger than 2 years of age. In addition, polysaccharide vaccines do not reduce nasopharyngeal colonization, and therefore do not lead to herd immunity.[43] By comparison, conjugate vaccines have a number of significant advantages (Table 3). They generally induce longer term protection, reduce nasopharyngeal carriage and are not associated with hyporesponsiveness after booster doses.[45,47] Although the currently available quadrivalent meningococcal conjugate vaccine is not immunogenic in infants,[48] Phase II and III trials have shown that MenACWY-CRM, an investigational quadrivalent meningococcal conjugate vaccine, is well tolerated and immunogenic in infants (Table 4).[49-51] In the context of travel medicine, reduction in carriage is particularly relevant to Hajj pilgrims in order to prevent infection of close contacts on their return from this high-risk event, and it should be made clear that quadrivalent conjugate vaccination is the optimal policy for these travelers. Finally, with the shorter period of protection and the possibility of hyporesponsiveness to repeated doses of polysaccharide vaccine,[46] conjugate vaccination would also be the optimal policy for students, frequent travelers and military personnel, potentially limiting the need for repeated doses over a number of years. The Advisory Committee on Immunization Practices (ACIP) now recommends the quadrivalent conjugate vaccine for all adolescents (11-18 years of age) and anyone 2-55 years of age at

increased risk of disease.[33,52,53] Although college-age students are at increased risk of meningococcal disease, they do not prioritize vaccinations and are not always compliant with vaccine recommendations. In 2007, despite ACIP recommendations, quadrivalent meningococcal conjugate vaccine coverage in the USA was only 32.4%.[54] Visits to the travel clinic may provide an opportunity to discuss the risks of meningococcal disease and the benefits of vaccination, particularly for this age group. Travel to high-risk destinations, such as the meningitis belt or areas with currently ongoing outbreaks, is an indication for vaccination. The extended protection that might be provided by conjugate vaccines means that the benefits to the subject are likely to extend beyond their immediate travels and should provide protection for a number of years, covering potential future domestic and travel exposure, even to countries with disparate disease epidemiology.
Conclusion

Meningococcal disease is an unpredictable and devastating disease that occurs worldwide, yet it remains neglected by travel medicine providers and travelers alike. Incidence rates vary across regions, with particularly high incidence rates in the African meningitis belt and among certain high-risk groups, such as Hajj pilgrims. A visit to the travel clinic provides an opportunity to administer such routine vaccinations independent of the travel destination, but in particular for those who do travel to high-risk destinations. While the risk of meningococcal disease to travelers visiting an individual country with no outbreak is relatively low, a proportion of individuals are regular travelers throughout the year. Their risk and need for vaccination should be calculated not on the basis of each individual visit, but as an overall risk. Many European countries offer the monovalent serogroup C conjugate vaccine as a routine vaccination to children and as a catch-up dose for adolescents.[55] However, this vaccine does not protect against other serogroups that can be encountered in destinations beyond Europe, and a quadrivalent meningococcal vaccine should therefore be used. While all four serogroups (A, C, W-135 and Y) may not be present at a particular travel destination, the quadrivalent vaccine can provide added protection, as meningococcal disease is dynamic and the emergence of an atypical serogroup to that region can arise. Travelers also need to be aware of other serogroups, such as B and X, which are not covered by any meningococcal vaccine formulation; for example, although serogroup B is covered in a vaccine developed for New Zealand, this is strain specific[56] and will not necessarily provide protection for any other global outbreaks of serogroup B. Given the high case-fatality rate, recent changes in travel patterns and geographical distribution of a wide range of serogroups that cause meningococcal disease, the nature of international travel requires broad protection against as many meningococcal serogroups as possible for all ages. As quadrivalent meningococcal conjugate vaccines offer the broadest, most durable and most effective protection, they are the preferred option over polysaccharide vaccines. However, conjugate vaccines are not yet available in all regions, which means that current vaccination strategies are suboptimal. Wider availability of conjugate vaccines will provide broader protection for those previously unvaccinated, for those who have previously received monovalent vaccine against serogroup C, and also for those who have previously received the polysaccharide meningococcal vaccine.

Awareness needs to increase about the risk of meningococcal disease and availability of vaccines among both practitioners and travelers.
Expert Commentary & Five-year View

The spread of meningococcal disease can be facilitated by the rapid increase in international travel to areas in which the disease is endemic. Travelers need to be aware of the risk of meningococcal disease and take appropriate precautions ahead of travel. In the next 5 years, quadrivalent conjugate vaccines should be available for all age groups to provide broad protection against meningococcal disease. The ability to offer protection to all age groups will also allow parents to travel with young children under 2 years of age, rather than delaying travel to countries with current outbreaks of meningococcal disease, as is recommended at the present time. Serogroup B vaccines should also be available to provide further protection against this important cause of meningococcal disease. With vaccines to protect against the five serogroups that are responsible for most cases of meningococcal disease, reducing disease incidence becomes a realistic possibility. With an increased awareness of the disease among travel medicine providers, this may mean that routine vaccine recommendations for travelers will include meningococcal disease.
Sidebar: Key Issues Key Issues
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Routine vaccinations in a traveler's home country cannot ensure protection at their destination. Meningococcal disease remains neglected by travel medicine providers and travelers alike. Increased disease awareness of meningococcal disease and the need for vaccination is required. The incidence of meningococcal disease varies greatly depending on destination, duration of travel and social behavior during travel. The broadest protection against meningococcal disease is offered by quadrivalent meningococcal vaccines.