Abstract
The trivalent seasonal influenza vaccine is expected to provide optimum protection if the vaccine strains match the circulating strains. The effect of worldwide mismatch between the vaccine strains and extant strains on travelers attending Hajj pilgrimage is not known. Annually 2-3 million Muslims coming from north and south hemispheres congregate at Hajj in Mecca, Saudi Arabia, where intense congestion amplifies the risk of respiratory infection up to eight fold. In order to estimate, to what extent mismatching increases the risk of vaccine failure in Hajj pilgrims, we have examined the global data on influenza epidemiology since 2003, in light of the available data from Hajj. These data demonstrate that globally mismatching between circulating and vaccine strains has occurred frequently over the last 12 years, and the mismatch seems to have affected the Hajj pilgrims, however, influenza virus characteristics were studied only in a limited number of Hajj seasons. When the vaccines are different, dual vaccination of travelers by vaccines for southern and northern hemispheres should be considered for Hajj pilgrims whenever logistically feasible. Consideration should also be given to the use of vaccines with broader coverage, i.e., quadrivalent, or higher immunogenicity. Continuous surveillance of influenza at Hajj is important.
Introduction
According to the World Health Organization (WHO), influenza affects between 5% and 10% adults, and 20% to 30% of children each year leading to 3 to 5 million severe illnesses, and 250,000 to 500,000 fatalities (http://www.who.int/influenza).
Of the 3 influenza virus types (A, B, and C), epidemiologically only types A and B are important.Citation1 In recent years, 2 major subtypes of influenza A (H1N1 and H3N2) and 2 lineages of influenza B (Yamagata and Victoria) have been circulating.Citation2 The current seasonal trivalent influenza vaccine (TIV) includes one strain of A/H1N1, one strain of A/H3N2 and a strain from one of the 2 lineages of influenza B. Vaccination has been a key recommended measure against influenza,Citation3,4 however, due to antigenic drift, novel strains are generated against which many people lack immunity. The vaccine is updated annually, based on the most likely circulating strains. Vaccination is moderately effective against virologically proven influenza and prevents both influenza symptoms and work days lost.Citation3,5 The dogma is that vaccine strains should resemble the circulating influenza strains in order to provide optimum protection. Based on a meta-analysis of 90 studies, the efficacy of influenza vaccine in healthy adults is 62% (95% CI 52% to 69%) when the vaccine strains and circulating strains are matched, and 55% (95% CI 41% to 66%) when matching was absent or unknown.Citation5 The more the mismatch, the greater is the burden of influenza. Data from a study conducted in Taiwan between 1999/2000 and 2006/07, showed that as the isolation rate of vaccine-mismatched influenza A (H3N2) increased, the monthly pneumonia and influenza mortality rates elevated.Citation6
Influenza is an important threat for attendees of mass gatherings. Hajj pilgrimage is one of the largest annual mass gathering events in the world. As a consequence of intense congestion and congregation of around 3 million Muslims from north and south hemispheres, the risk of respiratory tract infection (RTI) is amplified up to 8 times.Citation7-9 Indeed, RTIs are the commonest medical presentation and pneumonia is the leading cause of hospitalization at Hajj.Citation7,10 Influenza is one of the most common causes of viral RTIs among Hajj pilgrims, and the attack rate of laboratory-proven influenza among symptomatic Hajj pilgrims ranges between 4% and 15%.Citation10,11 Seasonal influenza vaccine is recommended by the Saudi Arabian authorities for all Hajj pilgrims, particularly those who are at a higher risk of severe complications;Citation12 and the vaccine uptake has notably increased in the last decade from 27.3% in 2005 to > 80% in 2014 among pilgrims from industrialized countries.Citation13 However, despite vaccination, influenza is reported among Hajj pilgrims. For instance, during the 2005 Hajj, 29% (8 of 28) UK pilgrims with confirmed influenza had the vaccine before their travel.Citation14 Poor matching between vaccine strains and circulating strains is attributed to vaccine failure.Citation15 However, it is not known to what extent mismatching increases the risk of vaccine failure in Hajj pilgrims. Here we aim to describe the epidemiology of circulating influenza strains worldwide and assess the implications of strain mismatching on Hajj pilgrims.
Methods
Data for this discussion were collected from various sources. Influenza surveillance data were collected for both hemispheres from 2003, because this was the time when the surveillance of viral RTIs among Hajj pilgrims was intensified in response to the SARS outbreak in East Asia and elsewhere. For northern hemisphere, annual influenza activity reports from the US Centers for Disease Control and Prevention (CDC) (http://www.cdc.gov/mmwr) were the main source, while for the southern hemisphere, Australian Influenza Surveillance Report and Activity Updates (http://www.health.gov.au/flureport) were the key sources. For each season in both hemispheres, data on antigenic characteristics of the viruses were collated and compared to the vaccine strains recommended by the WHO. Mismatching or ‘poor matching’ was defined if the circulating strains were totally different, or showed substantially reduced titer against the vaccine strains. The proportion of matching and mismatching between vaccine strains and extant strains is presented by bar chart ().
Figure 1. Matching and mismatching between circulating strains and vaccine strains of influenza in northern hemisphere.
Figure 2. Matching and mismatching between circulating strains and vaccine strains of influenza in southern hemisphere.
To explore the effect of mismatching on the epidemiology of influenza at Hajj, systematic searching of databases (mainly PubMed, and Saudi Epidemiology Bulletin (http://seb.drupalgardens.com) was done. Particular emphasis was given to the Hajj year 2003 and onwards. We have compared the extent of strain matching and mismatching at Hajj and evaluated the impact of mismatching on influenza burden among Hajj pilgrims.
Recommended vaccine strains in both hemispheres
Based on global influenza surveillance data, the WHO biannually recommends the influenza vaccine individually for north and south hemispheres. The recommended strains over 12 recent years are shown in ; vaccine strains were similar for both hemispheres in 4 seasons, and interestingly changes in the vaccine strains for southern hemispheres almost always followed the changes in vaccine strains in the previous season of northern hemisphere. For example, in February 2012, WHO replaced the northern hemisphere vaccine strain A/Perth/16/2009 (H3N2)-like virus by influenza A/Victoria/361/2011 (H3N2)-like virus, and influenza B/Brisbane/60/2008-like virus by influenza B/Wisconsin/1/2010-like virus; these changes were reflected in the southern hemisphere vaccine strains later that year. Similar phenomena repeated 8 times in the last 12 y. Conversely, changes in vaccine strains in the northern hemisphere followed the change in southern hemisphere vaccine strains in 4 seasons.
Table 1. Recommended influenza vaccine strains by WHO for northern and southern hemispheres since 2003.
Northern hemisphere
Between 2003 and 2014, influenza A was the predominant circulating type in all seasons in northern hemisphere (). Influenza A/H3N2 was the commonest subtype in 7 seasons and A/H1N1 was predominant in 4 seasons including the influenza pandemic in 2009. Interestingly, in the seasons 2007-2008, both subtypes of influenza A and a strain of influenza B belonging to Yamagata lineage circulated in similar proportions.
In three out of 7 seasons (2003/04, 2004/05 and 2014/15) when influenza A/H3N2 was dominant, a majority of the circulating H3N2 strains did not match with the vaccine strains. Also when H3N2 was not the dominant strain, substantial mismatching occurred in 2 seasons (2006/07 and 2007/08). On the other hand, the vaccine strains of H1N1 matched the circulating strains in all seasons, except for the 2009/10 pandemic season. Although influenza B was relatively less common, the vaccine strains did not match the circulating strains in 6 seasons (2003/04, 2005-2009 and again in 2011/12).
Considering all 3 strains in the recommended vaccine, a mismatch of at least 40% was observed in 7 seasons including the pandemic year (). Mismatching was more frequent during the pre-pandemic era but occurred again in the last season 2014/15.
Southern hemisphere
Overall, data for the southern hemisphere were more limited, and detailed information on matching between circulating and vaccine strains were not consistently available. The available data suggest that like the northern hemisphere, influenza A was the predominant type, except in the year 2008 when influenza B was dominant. Influenza A/H3N2 was the commonest strain in 6 seasons (from 2003 to 2007, and 2012) while influenza A/H1N1 was the prevalent strain in the other 5 seasons including the influenza pandemic year 2009.
Based on available data on circulating influenza strains in southern hemisphere, it is clear that the degree of matching and mismatching was variable, and differed by year. The proportion of overall matching was as high as 68% in 2010, and lowest (3%) in 2003. Similarly, matching and mismatching for each strain also varied. For instance, 97% of the circulating strains of influenza A/H3N2 in 2003 mismatched with the vaccine strains, while about 67% of circulating strains of A/H3N2 in the following season, 2004, matched the vaccine stains.
Influenza at Hajj
Hajj takes place in the last month of the Arabic calendar which is about 10 d shorter than the Gregorian calendar. Thus, according to the Gregorian calendar, Hajj advances by 10 d (at times 11 days) each year. Since 2003 this gathering has been taking place in the autumn/winter season of the northern hemisphere (i.e., between October and January), thus providing pilgrims with an opportunity to be vaccinated before traveling. Based on available surveillance data from Hajj (), the circulating types of influenza at Hajj was similar to the circulating types worldwide in 4 seasons (2004/05, 2005/06, 2011/12 and 2013/14), but not in the other seasons. For instance, although influenza A was the commonest type in 2010/11 season both at Hajj and worldwide, when it comes to subtype, influenza A/H1N1 was the most dominant subtype at Hajj (39%), while globally, influenza A/H3N2 was the most prevalent subtype (45%). Antigenic characterization of influenza viruses has been studied infrequently at Hajj (being done in the years 2004, 2005, 2010 and 2014), this has demonstrated that the circulating strains did not match with the vaccine strains of the corresponding years. For example, influenza B-Sichuan was the predominant strain at the Hajj in 2004 and kept circulating until the Hajj in 2005, and again in 2010, but the corresponding vaccine strains for those years were different ().
Influenza is reported among vaccinated pilgrims. As shown in , between 3% and 14% of symptomatic vaccinated pilgrims had laboratory-proven influenza in 2005, 2006 January, 2006 December and 2009. One study conducted at Hajj (in January 2004) noted that none of the vaccinated pilgrims in the study had influenza during Hajj.Citation16
Table 2. The circulating influenza viruses during Hajj since 2003.
Discussion
These data indicate that mismatching between circulating influenza strains and vaccine strains that occurs globally affect the Hajj pilgrims and therefore supplementary preventive measures would be beneficial for travelers to this high risk setting. Mismatching globally has been observed in a number of studies: in a meta-analysis of 35 studies involving 53 datasets, mismatching was recorded in 30 data sets.Citation17 In another analysis, different lineages of influenza B, opposite to the vaccine lineage, were responsible for 42% of all influenza B infections throughout 12 seasons since 1992 indicating that a quadrivalent vaccine with strains from both lineages of influenza B would be beneficial.Citation18
Hajj is a unique mass gathering event where pilgrims from different hemispheres congregate in one place, and crowding increases the likelihood of emergence of reassortant influenza virus that in turn may spread rapidly across the globe.Citation19 A recent meta-analysis has shown that influenza vaccine is still effective against laboratory-confirmed influenza at Hajj (risk ratio 0.56; 95% CI 0.41-0.75; p < 0.001).Citation20 This is supported by a systematic review of randomized clinical trials which has shown that despite mismatching TIV was efficacious against laboratory-confirmed influenza with the pooled efficacy of 56% (95% CI 43% to 66%).Citation21 However, optimum benefit from influenza vaccine is obtained when the degree of matching is high. For instance, when the uptake of matched influenza vaccine is high, unvaccinated individuals can have protection through herd immunity.Citation22,23
Mismatching underpins the importance of using additional preventive measures against influenza. When the vaccines are different, dual vaccination of travelers by both southern and northern hemispheres' vaccines, if logistically achievable, is a concept that has been raised by travel physicians for a decade.Citation24,25 Indeed, 82% of active health professionals in the field of travel medicine in the USA were interested to get the southern hemisphere vaccine in their travel clinics.Citation26 Such a strategy, could benefit Hajj and Umra pilgrims.Citation27
Vaccines with broader coverage or higher immunogenicity could be useful for Hajj pilgrims. Besides quadrivalent vaccine which would offer wider protection when the viruses of B lineages mismatch or co-circulate, more immunogenic vaccines, such as adjuvanted or high antigen dose vaccine, can also provide added benefits to immunosenescent individuals including elderly individuals.Citation28,29
Targeted use of antiviral prophylaxis, for instance, a combination of ‘treatment of cases’ and ‘ring prophylaxis of contacts’ is considered to be a feasible and economically sustainable strategy for attendees of mass gatherings, including Hajj pilgrims.Citation30 Use of facemasks is another potentially useful strategy, but the role is not yet proven; a large trial is currently underway.Citation31 Use of hand hygiene should be encouraged with an aim to improve general hygiene, and to reduce the transmission of infectious diseases (not just influenza) in the crowded milieu of Hajj. This would also complement Muslims' ablution before prayers 5 times a day.Citation32
It is unclear whether a high uptake of influenza vaccine contributes substantially to the appearance of mismatching. Most importantly, antigenic characterization of the circulating influenza strains at Hajj compared to the recommended vaccine strains was conducted only infrequently. Further research and continuing surveillance could add to our knowledge about the circulating influenza during Hajj and help identify effective interventions against it. To this end, led by Australian researchers, a large multinational test-negative case-control study is being undertaken at Hajj which could inform the policy.
Disclosure of potential conflicts of interest
Professor Robert Booy has received funding from Baxter, CSL, GSK, Merck, Novartis, Pfizer, Roche, Romark and Sanofi Pasteur for the conduct of sponsored research, travel to present at conferences or consultancy work; all funding received is directed to research accounts at The Children's Hospital at Westmead. The other authors have no competing interests to declare.
Funding
GK is supported by NHMRC Health Early Career Fellowship (1054414). This work is part funded by the National Health and Medical Research Council (NHMRC) Center of Research Excellence (CRE) in Population Health Research titled ‘Immunisation in under Studied and Special Risk Populations: Closing the Gap in Knowledge through a multidisciplinary Approach’.
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