Epidemiology of vaccine-preventable diseases in Japan: considerations for pre-travel advice for the 2019 Rugby World Cup and 2020 Summer Olympic and Paralympic Games

Introduction In 2019 and 2020, Japan will host two international sporting events estimated to draw a combined 22 million visitors. Mass gatherings like these ones increase the risk of spread of infectious disease outbreaks and international transmission. Pre-travel advice reduces that risk. Methods To assist ministries of health and related organizations in developing pre-travel advice, we summarized national surveillance data in Japan (2000–2016, to the extent available) for rubella, invasive pneumococcal disease, measles, non-A and non-E viral hepatitis, hepatitis A, invasive Haemophilus influenzae disease, tetanus, typhoid fever, invasive meningococcal disease, Japanese encephalitis, influenza, varicella, mumps and pertussis by calculating descriptive statistics of reported cases and reviewing trends. (See Annex A for details of reviewed diseases.) Results Our findings showed notable incidences of rubella (1.78 per 100 000 person-years), influenza (243.5 cases per sentinel site), and mumps (40.1 per sentinel site); seasonal increases for influenza (November–May) and Japanese encephalitis (August–November); and a geographical concentration of Japanese encephalitis in western Japan. Measles cases decreased from 11 013 in 2008 to 35 in 2015, but outbreaks (n = 165 cases) associated with importation occurred in 2016. Though invasive meningococcal disease incidence was only 0.03 per 100 000, international transmission occurred at a mass gathering in Japan in 2015. Discussion Ministries of health and related organizations should use these findings to develop targeted pre-travel advice for travellers to the 2019 Rugby World Cup and the 2020 Summer Olympic and Paralympic Games, especially for mumps, measles, rubella, influenza, and meningitis. Travellers with increased exposure risk should also be advised about hepatitis A and Japanese encephalitis.

T he 2019 Rugby World Cup will occur from 20 September to 2 November throughout Japan, and the 2020 Summer Olympic and Paralympic Games will happen in Tokyo from 24 July to 6 September. These mass gatherings (MGs) are estimated to attract 22 million visitors to Japan. 1 MGs like these can strain resources of the host country and have been associated with disease outbreaks and the international spread of disease. [2][3][4] The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) recommend travellers seek advice from health professionals before travelling to an MG. 5, 6 This strategy has been associated with a twofold increase in vaccinations among Hajj pilgrims who seek such advice compared to those who do not. 7 Up-to-date vaccination for all vaccine-preventable diseases (VPDs) is the best way to prevent illness, outbreaks and the international spread of disease. To assist ministries of health and other organizations in developing targeted pre-travel advice for these MGs, we aimed to summarize the recent epidemiology of selected VPDs in Japan. WPSAR  For the period reviewed, approximately 79% of the reported rubella cases occurred in 2013 (n = 14 344).
Since April 2006, the routine vaccination schedule has included two doses of measles-rubella (MR) vaccine: the first dose at 1 year of age and the second dose less than 1 year before entering primary school (typically age 5 or 6). Prior to 2006, a single rubella dose had been routine for 11-12-year-old girls since 1977. Doses for both sexes aged 12-89 months and for boys 11-12 years old were added in 1995.
Since November 2013, routine vaccination has included four doses of 13-valent pneumococcal conjugate vaccine (PCV13) for children aged 2-59 months. PCV13 replaced PCV7, which had been subsidized since November 2010 and was routine since April 2013 for children <24 months old. Routine immunization with 23-valent pneumococcal polysaccharide vaccine for adults aged ≥65 years began in October 2014 after having been available on a voluntary basis since 1988.

METHODS
We selected diseases based on frequency, severity and potential immunity (i.e. likelihood that foreign travellers to Japan would have developed immunity against the disease before visiting Japan because of wide circulation of the pathogen or global vaccination trends) among visitors to Japan. We obtained data from the National Epidemiological Surveillance of Infectious Diseases (NESID) system for a period of at least eight years up to the latest finalized data (for most diseases 2015; years inclusive unless otherwise noted). National notifiable disease surveillance comprises passive case-based reporting from all health-care facilities in Japan. For this work, we selected rubella, invasive pneumococcal disease, measles, viral hepatitis non-E and non-A, hepatitis A, invasive Haemophilus influenzae disease, tetanus, typhoid, invasive meningococcal disease and Japanese encephalitis. NESID also has weekly sentinel surveillance from approximately 3000 paediatric clinics for some diseases. Of these, we selected varicella, mumps, pertussis and influenza. An additional 2000 adult outpatient clinics report influenza.
We gathered data on case totals by sex, age group, prefecture, and week and year of report. When available, we obtained clinical disease classifications (e.g. modified measles), vaccination history, the suspected location or route of infection and laboratory results. For influenza and varicella, we obtained counts of hospitalized cases with laboratory evidence of infection. Influenza cases have been reported from hospitals with more than 300 beds since 2011 and varicella cases from all hospitals since September 2014.
We calculated totals, proportions, ranges, and incidence per 100 000 person-years using annual population estimates from Japan's Statistics Bureau, 8 applying relevant proportions for incomplete years. For sentinel diseases, we calculated mean cases reported per sentinel site because catchment population sizes were unavailable. To further contextualize the findings, we briefly described current vaccination policies. For detailed case definitions and additional disease information, see Annex B.
Griffith et al Recent epidemiology of vaccine-preventable diseases in Japan See rubella vaccination (above). Additionally, a single measles vaccine dose has been available for children aged 12-71 months since 1978 and was expanded to 89 months in 1995.
No vaccine has been approved for typhoid fever in Japan. Individual physicians may import and administer the vaccine without government reimbursement or, in the case of adverse events, patient compensation.
The meningococcal conjugate vaccine (MCV4) became available for voluntary use in May 2015.
Four doses of inactivated JE vaccine are included in the routine schedule: three between 6 months and 7½ years of age and one between 9 and 13 years of age.
The routine schedule has included three doses of hepatitis B vaccine for infants aged <12 months since October 2016. Voluntary maternal vaccination is also available.
Since March 2013, two-dose inactivated hepatitis A vaccination has been available on a voluntary basis for all ages. Previously it had been available for those aged ≥16 years.
Since April 2013, four doses of H. influenzae type b vaccine have been routine for those aged <59 months. Voluntary vaccination for children <5 years had been approved since December 2008; government financial assistance was added in November 2010.

Tetanus (2006-2015)
Between 89 and 128 cases of tetanus were reported each year with consistent increases during epidemiologic weeks 19-29. Cases were mostly aged ≥55 years (85%; n = 984). All prefectures reported cases. The incidence of tetanus in Japan for the reviewed period was 0.09 per 100 000 person-years (n = 1158).

DISCUSSION
Most VPDs in Japan present low risk for the majority of travellers attending the 2019 Rugby World Cup and 2020 Tokyo Summer Olympic and Paralympic Games. Occurrence has either declined or maintained a low level. Rubella, mumps, influenza, measles and IMD, however, present more complicated pictures. Hepatitis A and JE may pose higher risk for some travellers as discussed below.
Due to the epidemiology of rubella, mumps and influenza in Japan, these diseases should be prioritized for pre-travel advice. Rubella surged in 2013, likely related to undervaccination among adult males. A rubella antibody seroprevalence study in Japan in 2016 suggested that males 35-54 years old had less immunity than women for that age group; the gap narrowed to <10 percentage points for those aged 20-34 and ≥55. 10 The vaccine was introduced in 1977 for 11-12-year old girls and was expanded in 1995 to boys 11-12-year-old and both sexes 12-89 months old. 11 For mumps, 4-5 year peak cycles are also likely related to undervaccination. Recent mumps vaccination

Influenza (2000-2015)
All influenza seasons reviewed, except 2009, began in November, peaked in late January to mid-March and finished in May. Sentinel sites reported 18 508 470 cases, averaging 243.5 annual cases per sentinel site (see Table 2 Since October 2014, the routine vaccination schedule has included two varicella vaccination doses for children between 1 and 2 years old. The vaccine is available on a voluntary basis for those aged ≥2 years.

Mumps (2000-2015)
Mumps cases in Japan peaked in 2001 (84.4 cases per sentinel site), 2006 (66.6 cases per site) and 2010 (59.3 per site) without seasonality. No prefecture consistently reported high numbers of cases. Cases aged 2-5 years accounted for 57% (n = 1 048 851) and males for 54% (n = 1 051 903) of cases. In total, 1 963 679 cases even when domestic incidence is low; pre-travel advice should include ensuring up-to-date vaccinations, frequent handwashing and avoiding contact with items that contain others' saliva or respiratory droplets as much as possible.
Travel advisers should also consider individual traveller behaviours and itineraries. Hepatitis A transmission in Japan has primarily been linked to food, particularly shellfish and seafood. 19 This information was obtained through self-reporting, which can be biased by social desirability. In 2017, outbreaks of hepatitis A among men who have sex with men were reported in both Europe and the Americas. 20 Individuals who engage in activities that put them at risk for hepatitis A should be advised on preventive measures like vaccination, safesex practices, handwashing and food selection. Travellers intending to visit western Japan, especially non-urban areas, should consider JE vaccination and mosquito-bite prevention.
Though not reviewed, rotavirus disease tends to increase from February to May, outside the scheduled MG periods, and tuberculosis has been decreasing since 1999 with 14.4 new cases per 100 000 person-years in 2015. 21,22 The selection of diseases for this work was largely based on expert opinion and discussion among leaders within the Infectious Diseases Surveillance Center (IDSC) at NIID. We could have unintentionally left out diseases that might affect travellers visiting the upcoming MGs. Most passive disease surveillance systems may be limited by incomplete reporting, lack of representativeness or failure to identify outbreaks. 23 NESID may also suffer coverage in Japan has been 30-40%. 12 Vaccinations against mumps were voluntary until 1989 when MMR became routine; due to concerns with mumps componentrelated aseptic meningitis, MMR was replaced with a voluntary monovalent mumps vaccination in 1993. Mumps outbreaks with up to 214 cases have been reported at MGs in Europe. 13,14 For influenza, seasons typically occur outside of when MGs are scheduled to occur in Japan. Nevertheless, travellers from the southern hemisphere leaving during its influenza season could import the virus and transmit it to northern hemisphere attendees who have not yet been vaccinated. To prevent mumps, rubella and influenza, advice should include ensuring up-to-date (or for influenza early) vaccinations, practising proper hygiene and recognizing and reporting signs and symptoms of these diseases.
Although case numbers have been low, measles and IMD outbreaks with international transmission suggest these diseases should also be considered during pre-travel consultations. The endemic measles strain (D5) was last detected in Japan in 2010, and WHO verified elimination in 2015. 15 In 2016, however, measles outbreaks occurred in Japan. All were linked to importation, including an outbreak at an international airport. Most cases were undervaccinated. 16 For IMD, authors have noted Japan's low incidence compared to other developed countries. 17 A 2015 outbreak with six IMD cases was detected after an international youth event in Japan with more than 33 000 participants from 162 countries. All cases were from Europe, one of which did not attend the event. 18 These events show how importation can cause outbreaks * Those aged >65 and those 60-65 with certain chronic diseases or immunocompromised conditions.

Funding
This study was partly supported by the Research on Emerging and Re-emerging Infectious Diseases and Immunization (H30-shinkougyousei-shitei-004). these limitations. Additionally, it lacks catchment population data for sentinel surveillance, limiting the ability to estimate sentinel disease incidences. Nonetheless, NESID comprises the most standardized, robust national data available. We believe comparisons across time and place are valid and sufficient for our purposes. In most cases, we attempted to review 10 years of data. For some diseases the introduction or change of reporting requirements prevented that. Readers should conclude with caution when considering diseases with very short reviewed periods.
Few outbreaks associated with sports-based MGs have been reported in literature. Most were reported from the United States of America 24,25,26 with one from the United Kingdom of Great Britain and Northern Ireland, 27 limiting generalization. Their findings nevertheless imply important considerations: outbreak risk at sports-based MGs is low but not null; outbreaks occur among athletes and nonathletes, associated and unassociated persons and populations of high and low vaccination coverage; importation can spark an outbreak even in low-incidence countries; and, as noted in one article, 25 the difficulties of conducting surveillance on international visitors could mean misunderstanding the size or nature of an outbreak or missing an outbreak entirely. Ministries of health, organizations, health-care providers and travellers should ensure up-to-date vaccinations of travellers before they attend MGs, and they should also promote and support travellers carrying updated vaccination records to assist the home country with any potential case or outbreak investigations.
As we have outlined, up-to-date vaccinations with additional preventive measures should be included in pretravel advice for visitors to the 2019 Rugby World Cup and 2020 Tokyo Summer Olympic and Paralympic Games, specifically for mumps, measles, rubella, influenza and IMD for all travellers and for hepatitis A and JE for travellers at higher risk. When providing advice, health professionals should also inform travellers about the role they could play in transmitting or preventing the transmission of disease to MG attendees from across the world.

Conflicts of interest
None.