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Abstract
Recent progress in the Japanese immunization program has partially closed the "vaccine gap," i.e., the deficiencies in that program relative to immunization programs in other developed countries. During the last several years, seven new vaccines (12 new products, excluding influenza vaccines) have been introduced in Japan. Five of these new vaccines are produced outside Japan and four are now included as routine vaccines in the National Immunization Program, which is a new development in the licensing and financial support of imported vaccines. However, along with this progress, important concerns have arisen regarding the Japanese immunization program. A rubella epidemic among adults, in 2012-2013, resulted in more than 40 cases of congenital rubella syndrome as of March 2014. In addition, the temporary withdrawal of the active governmental recommendation for human papilloma virus vaccines, in 2013-2014, highlighted challenges in the current Japanese immunization system. Furthermore, some important vaccines - including vaccines for hepatitis B virus, mumps, varicella, and rotavirus - are still not included in the National Immunization Program and have been categorized as voluntary vaccines since their introduction. The possibility of their inclusion in the National Immunization Program remains a matter for discussion. We hope that future initiatives will further address the vaccine gap and protect Japanese children from vaccine-preventable diseases.
Full text
Introduction
Recent progress in the immunization program of Japan has begun to close the "vaccine gap," a term used during the last two decades to refer to the deficiencies of that program relative to programs in other developed countries [1] . Seven new vaccines (12 new products, excluding influenza vaccines) have been introduced in Japan since 2008 (Table 1 ): a Haemophilus influenzae type b (Hib) vaccine, 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13), rotavirus vaccines (monovalent [RV1] and heptavalent [RV5]), human papillomavirus (HPV) vaccines (bivalent [HPV2] and quadrivalent [HPV4]), an inactivated Salk-derived polio virus vaccine (wIPV), diphtheria, tetanus toxoid, acellular pertussis, and inactivated Sabin-derived polio vaccines (DTaP-sIPV, 2 products), and inactivated Vero cell-derived Japanese encephalitis vaccines (JE, 2 products). Among them, after licensure, the wIPV, DTaP-sIPV, and JE vaccines were introduced to the National Immunization Program (NIP) as routine immunizations to replace the oral polio vaccine, DTaP, and inactivated mouse brain-derived JE vaccine, respectively. In January 2011, a temporary national budget was created to support the costs of the Hib, PCV7, and HPV vaccines, and they have been included in the NIP since April 2013. Later, PCV7 was uneventfully replaced by PCV13 in November 2013. Five of the seven vaccines (8 of the 12 products) are produced in foreign countries, which is a new development in the licensing and support of imported vaccines in Japan.
Vaccine availability is improving, recognition of vaccine-preventable diseases (VPD) is increasing, and more vaccines are now included in the NIP; however, some concerns remain regarding immunization, which indicates that the current Japanese immunization system needs further improvement. The Japanese rubella epidemic in 2012-2013, which mainly affected adults [2] , resulted in more than 40 cases of congenital rubella syndrome, as of March 2014. Most of the people who developed rubella were men aged 20-40 years, as this group had not received the rubella vaccine during their youth [3] . Vaccination rates among the susceptible population remain low because catch-up vaccines for targeted individuals are categorized as voluntary and are an out-of-pocket expense. Many local governments offered financial support for vaccines in targeted populations, which increased vaccination rates. However, the shortage of vaccines developed after the demand increased for rubella vaccine and measles and rubella (MR) vaccine. Another important problem is that, due to reports of more than 30 cases of chronic pain syndrome, the government temporarily withdrew its active recommendation for HPV vaccines, beginning in June 2013. Unsurprisingly, immunization rates for HPV vaccines decreased sharply due to fears that the vaccines might cause adverse reactions/events.
In this review, we summarize recent progress and discuss current concerns regarding the Japanese immunization program.
Recent progress in the Japanese immunization program
Revision of the immunization law
In April 2013, the Japanese Immunization Law underwent major revision. The most important changes were (1) the inclusion of three new vaccines (the Hib, PCV7, and HPV vaccines) in the NIP and continuing discussion of including the remaining important vaccines in the NIP, (2) further government financial support for immunization, (3) changes in the timing of Bacille de Calmette et Guérin (BCG) vaccination, (4) establishment of a new committee for national immunization policy, (5) legislative authorization to launch a vaccine adverse events reporting system, and (6) development of a national immunization policy.
Introduction of new vaccines to the NIP
Vaccine licensing has traditionally been slow in Japan [1] , particularly for vaccines manufactured in foreign countries. As compared with the United States, the Hib vaccine was introduced 21 years later (1987 vs. 2008) and the PCV7 vaccine was introduced 10 years later (2000 vs. 2010) in Japan. However, as part of recent progress in vaccine licensing (Table 1 ), the government allocated a temporary national budget for the Hib, PCV7, and HPV vaccines in January 2012, and these three vaccines were included in the NIP when the law was revised. After fees were decreased for vaccination recipients, vaccination rates increased and the effectiveness of the vaccines was confirmed in data from selected populations [4] . Analysis of data on Hib infection before (2008-2010) and after (2012) government financial support shows that Hib meningitis and invasive diseases (excluding meningitis) decreased by 92% and 82%, respectively. Data on pneumococcal diseases during the same time periods show that pneumococcal meningitis and invasive diseases (excluding meningitis) decreased by 71% and 52%, respectively. The latest Japanese immunization schedule by the Japan Pediatric Society is shown in Table 2[5] , demonstrating that the schedule is similar to that of other developed countries.
These effectiveness data highlight the importance of vaccine availability and financial support [6] , which have led to high vaccination rates and lower incidences of invasive bacterial diseases among children. Additionally, as of September 2014 the government will include the varicella-zoster virus (VZV) vaccine (for children aged 1-5 years, 2 dose schedule) and 23-valent pneumococcal polysaccharide vaccine (for adults aged >=65 years) in the NIP. The VZV vaccine uses the Oka strain and was developed by Takahashi and colleagues in Japan in the early 1970s [7] . Its inclusion in the NIP was strongly desired by most Japanese pediatricians due to the clinical burden associated with VZV. The inclusion of new vaccines in the NIP is another step in addressing the vaccine gap.
New national budget for immunization
Previously, the law required that the immunization budget for vaccines be split evenly by the national and local governments. However, inadequate financial support from the national government was a serious problem, as it created a financial burden for local government. The revised law increases support from the national government, from 50% to 90%, thus decreasing the financial burden for local governments. We hope that this trend toward greater national support for immunization continues.
Changes in the timing of BCG vaccination
Japan is one of a few developed countries that vaccinate all children for BCG. The vaccine uses the Tokyo 172 strain and is administered by percutaneous, multi-needle puncture [8] . Universal immunization is considered necessary because the incidence of tuberculous diseases remains high; the incidence of new tuberculosis disease was estimated to be 16.7 cases/100,000 in 2012, which is 1.3-6.2 times the rates in other developed countries [9] . In the past, BCG vaccine was given within the first 4 years of life. In 2005, Japanese guidelines called for it to be administered with the first 6 months of life (earliest recommended age 3 months, generally age 3-5 months), to prevent tuberculous diseases in children, especially among infants and young toddlers. However, after the schedule change, national adverse reaction reports showed that cases of osteitis/osteomyelitis due to BCG increased from 1.2 per year (2001-2005) to 4.4 per year (2006-2010). Because of this increase in osteitis/osteomyelitis incidence and the recent introduction of new vaccines (which crowded the vaccination schedule during early infancy), the recommended timing for BCG vaccination was changed slightly, from within the first 6 months to within the first year (recommend vaccination period, age 5-7 months) (Table 2 ). In other countries, particularly developing countries, the BCG vaccine is given at birth. However, very early administration may increase the risk of disseminated diseases in children with immunodeficiency states such as severe combined immunodeficiencies, chronic granulomatous disease, and interferon-γ, and interleukin-12 receptor deficiencies [10] . The reasons for the increase in osteitis/osteomyelitis after the change in BCG timing are not known; thus, after the schedule change it is important to monitor the incidences of osteitis/osteomyelitis and tuberculous diseases before receiving BCG vaccination. Furthermore, the indications and timing of BCG vaccination need to be reconsidered in Japan, as the incidence of new tuberculous disease in large cities is almost three times that in rural areas.
Recent improvements in the Japanese immunization program
In addition to these new developments, several new movements are underway. First, the possibility of establishing a National Immunization Technical Advisory Group (NITAG) to address issues related to national immunization policy was discussed [11] . In 2008, the government launched the Vaccination Subcommittee of the Health Sciences Council to discuss reform of the current immunization law and NIP in Japan. Subsequently, along with changes to the immunization law, the newly reformed Immunization and Vaccine Committee of the Health Science Council was established with three subcommittees, on (1) basic immunization strategies and policies, (2) vaccine research and development, including production and distribution, and (3) adverse reactions. After the committee and subcommittees were established, initiatives to close the vaccine gap have been discussed more frequently. The Minister of Health, Labor, and Welfare is now required to consult the committee when a scientific opinion on immunization is needed. The meeting is open to the public and can be attended by a publically selected representative who has the right to speak during the meeting. Second, the law mandates the launch of a new system for reporting vaccine adverse events, which makes it possible to report adverse reactions that are directly related to vaccines and those that are unlikely to be related to vaccines. Third, the Japanese government has been stockpiling some strains of H5N1 influenza virus since 2006 to be ready to produce approximately 10 million doses of H5N1 vaccine every year. This is a new, proactive movement by the government showing the attitude to prepare for the future pandemic by H5N1 and other potential influenza virus. Finally, the government also developed both middle- and long-term national immunization policies, which clearly state that Japanese citizens should be vaccinated as protection against VPD. We hope that these new developments will help further improve the immunization law and NIP in Japan. Ideally, in the future the national government will provide the necessary vaccines to all children, at no expense to their guardians, to ensure that all children are protected from VPD.
Current concerns
Although there has been substantial progress in the Japanese immunization program, some important concerns remain.
The 2012-2013 Japan rubella epidemic
Since 2012, more than 16,700 rubella cases have been reported in Japan. The peak incidence was in May 2013, and more than 75% of cases were men, among whom 80% were aged 20-40 years. More than 40 confirmed cases of congenital rubella syndrome have been reported as of March 2014.
Explanation of this epidemic requires a discussion of the history of rubella vaccination policy in Japan. Between 1977 and 1989, the NIP called for administration of a single-antigen rubella vaccine to female junior high school students. In 1989, a measles, mumps, and rubella (MMR) vaccine was introduced in the NIP and targeted all children aged 1 year to less than 6 years. However, the MMR vaccine was withdrawn in 1993 because of a high incidence of aseptic meningitis related to the mumps component of the vaccine virus strain [12] . After that, the rubella vaccine was again given only to female junior high school students. In 1995, a revision of the vaccination law changed the status of all vaccines to strongly recommended but not mandatory; which weakened government encouragement of potential recipients to receive vaccines. On four occasions, the government subsequently repeated the temporary recommendations for different populations susceptible to rubella: among first- and second-year elementary school students (in 1995), first-year elementary school students (1996-1999), junior high school students without a history of rubella (2001-2003), and unvaccinated individuals aged 16-24 years (2001-2003). Finally, in 2006, an MR vaccine was introduced for administration at ages 1-2 years and 5-7 years. Because of a measles epidemic in 2007 in Japan [13] , a catch-up MR vaccination program was introduced for individuals who were aged 12-13 years or 17-18 years during the period from 2008 through 2012. However, no policy was introduced for susceptible individuals, especially men, who had not received rubella vaccine during their youth. During the recent rubella epidemic, 65% of cases were adults aged 20-40 years.
Currently, the rubella vaccine is given free-of-charge to children aged 1 year or 5-6 years; however, it is considered a voluntary vaccine for those outside this age range and must be paid for out-of-pocket. The cost of the rubella and MR vaccines is approximately US$ 50 and US$ 100, respectively. In addition, there has been a shortage of rubella vaccine due to the nationwide announcement of financial support from local governments for susceptible individuals. The shortage of vaccine became a major obstacle to achieving a high vaccination rate in this population. Furthermore, the concept of a catch-up schedule is not well understood in the general population. Although some local governments provide financial support, the strategies varied. Most local governments provided support for susceptible women who wish to become pregnant or individuals who are near pregnant women; only a few governments provided support for other susceptible individuals, including men. Ideally, strategies that include rubella vaccination for all susceptible individuals, at all ages and at no cost, are necessary in order to avoid another epidemic. Important considerations remain to be discussed, including the means, cost, and feasibility of vaccination.
Temporary withdrawal of the active recommendation for HPV vaccines, due to reports of chronic pain syndrome
The HPV2 and HPV4 vaccines were licensed in Japan in December 2009 and August 2011, respectively. More recently, a national temporary budget was approved to enable free vaccination of girls aged 9-14 years, which started in February 2012. Ultimately, the vaccines were included in the NIP when the immunization law was revised in April 2013. Although the introduction and financial support of these vaccines was approved comparatively quickly, 2 months after their introduction to the NIP the government temporarily withdrew its active recommendations regarding these vaccines, due to a growing number of reports (approximately 30 cases in June 2013) of vaccine recipients developing persistent pain and/or motor impairment after vaccination. Of note, most affected individuals developed the symptoms and signs before introduction of the vaccine to the NIP and reported these events to the government during the period of case accumulation. The government chose to withdraw its active recommendation for the vaccines until a causal relationship between the vaccines and these adverse events could be disproved. The symptoms were initially thought to be complex regional pain syndrome, which manifests as chronic pain after a needle stick (e.g., after blood collection or vaccination), trauma, or other procedures/events resulting in pain. However, the characteristics of the reported clinical manifestations vary, especially time from injection to onset of symptoms, which ranges from immediately after to 2 years after vaccination.
Several other differential diagnoses were proposed, including macrophagic myofasciitis [14] , fibromyalgia, and chronic fatigue syndrome. After announcement of the temporary withdrawal, the number of cases reported to the government increased to 121, as of September 2013.
Based on the data as of September, 2013, regarding pain-associated events, defined as global pain not limited to the vaccinated arm, 72 cases (1.02 cases/100,000 vaccinations) and 25 cases (1.34 cases/100,000 vaccinations) were reported among recipients of the HPV2 and HPV4 vaccines, respectively. In total, 97 cases were reported, and the median age of the vaccine recipients was 14 years. Regarding time from vaccination to onset of symptoms, 29% developed symptoms within 1 day after vaccination, 64% developed symptoms within 1 month, and the remaining 36% developed symptoms more than 1 month later. Regarding motor impairment (defined as motor impairment, impaired coordination or balance, gait disturbance, myoclonus, impaired motor function, or muscle weakness), 22 cases (0.31 cases/100,000 vaccinations) were reported among HPV2 vaccine recipients and 11 cases (0.59 cases/100,000 vaccinations) were reported among HPV4 vaccine recipients. In total, 33 cases were reported, and the median age of the recipients was 15 years. Regarding time from vaccination to onset of symptoms, 37% developed symptoms within 1 day after vaccination, 77% developed symptoms within 1 month, and the remaining 23% developed symptoms more than 1 month later.
After a detailed investigation of the reported cases, reviews of domestic and international data related to this topic, and interviews of domestic and international researchers in this field, the Committee on Vaccine Safety is close to a consensus opinion that the vaccines are safe and that the symptoms were most likely due to conversion disorder rather than to the vaccines, or adjuvants, themselves. Other conditions were ruled out, including neurologic diseases, toxin-mediated diseases, and immunologic disorders related to the vaccines. Although the relationship between psychological factors and complex regional pain syndrome is not well understood [15] , the government suspended its active recommendation of the HPV vaccine, in February 2014. In addition, the government designated 17 university hospitals to monitor and evaluate patients with chronic pain syndrome. During that period, information on the putative risks of the vaccines was widely disseminated on the internet and in the mass media, and it will therefore be some time before vaccination rates increase to former levels, even if the government reinstates its recommendation.
Adverse events temporally linked to administration of HPV vaccine have impeded or disrupted vaccination programs in other countries [16] . Because HPV vaccines are given to teenagers, who may be more sensitive and have more psychological distress as compared with younger and older people, it is important to monitor continuously the safety of HPV vaccines. In post-licensure surveillance, the safety of HPV vaccines has been confirmed in a number of countries, including the United States [17] , Australia [18] , and the Scandinavian countries of Denmark and Sweden [19] .
Remaining voluntary vaccines
Although the Hib, PCV13, and HPV vaccines were recently included among legally authorized vaccines, several important vaccines - including the mumps, VZV, hepatitis B virus (HBV), and rotavirus vaccines - continue to be categorized as voluntary vaccines, which are not regulated by Japanese law and require out-of-pocket payment. The current status of vaccines recommended for all children by the World Health Organization (WHO) [20] and VZV vaccine is summarized for several developed countries, in Table 3 . The critical issue is that differences in vaccine categorization lead recipients to regard voluntary vaccines as less important than recommended vaccines. This has resulted in low rates of receipt of voluntary vaccines and persistently high incidences of target diseases. For example, VZV infection is highly endemic in Japan, and an estimated 300,000 cases of VZV infection are due to low vaccination rates [21,22] . There have been reports of severe varicella complications [23,24] and frequent episodes of hospital-onset varicella [25] in Japan, which could have been prevented by vaccination. In addition, the burden for hospital treatment of patients with varicella is enormous [26] , as such treatment includes the costs for medical care and financial losses due to hospital ward closures, particularly hematology and oncology wards. Fortunately, VZV vaccine will be included in the NIP, starting from October 2014.
Mumps is also highly endemic in Japan, and many children develop complications of mumps infection, including hearing loss [27] . Japan is the only developed country in which the MMR vaccine is not available. The previous MMR vaccine was withdrawn after it was found to cause vaccine-related aseptic meningitis (due to the mumps component of the vaccine) in 1 case for every 500-900 vaccinations [12] . The vaccine was withdrawn from the market in 1993, and a mumps monovalent vaccine has been given as a voluntary vaccine since then. A new MMR vaccine is urgently needed for Japanese children, to prevent the complications of mumps.
Lack of combination vaccines
Only four combination vaccines are currently available in Japan: the DTaP-sIPV, DTaP, DT, and MR vaccines. Combination vaccines that contain the HBV, Hib, and IPV vaccines are currently used in other countries but are not available in Japan. The immunization schedule of the Japan Pediatric Society [5] recommends that the HBV, Hib, PCV13, DTaP-IPV, and RV vaccines be given at age 3 months. These vaccines require 4 injections and 1 oral vaccine to be given at one visit, which is not easy for 3-month-old infants, their caregivers, and medical personnel. If a more-valent combination vaccine were available, it would reduce the number of injections required, which would decrease the burden of pain for children and the workload for medical professionals. Combination vaccines increase vaccination rates, decrease costs and the workload for vaccine givers, and reduce the storage space needed for vaccines [28] . Further distribution of existing or newly developed combination vaccines will be of great benefit to recipients and medical professionals.
In conclusion, although the Japanese immunization program has progressed, additional improvements are necessary. We recommend that the immunization program be evaluated as part of national policy, that decision-making and evaluation of scientific evidence within the NITAG be more transparent, that medical professionals and the general public be given better information on the benefits and risks of vaccines, that voluntary vaccines be included in the NIP, and that combination vaccines be introduced and developed in Japan.
Acknowledgment
We would like to thank David Kipler for editing this manuscript.
Year licensed | Month licensed | Vaccines | Trade name | Foreign (F) or domestic (D) | In NIP (starting month, year) |
2008 | December | Haemophilus influenzae type b | Act-Hib | F | Yes (April 2013) |
2009 | June | Vero cell-derived, inactivated Japanese encephalitis | JEVIK V | D | Yes (June 2009) |
December | Divalent human papilloma virus | Cervarix | F | Yes (April 2013)* | |
2010 | February | 7-Valent conjugate pneumococcal | Prevenar | F | Yes (April 2013) |
2011 | April | Vero cell-derived, inactivated Japanese encephalitis | Encevac | D | Yes (April 2011) |
August | Quadrivalent human papillomavirus | Gardasil | F | Yes (April 2013)* | |
November | Monovalent rotavirus | Rotarix | F | No | |
2012 | July | Heptavalent rotavirus | Rotateq | F | No |
September | Salk-derived, inactivated polio | Imovax | F | Yes (September 2012) | |
November | Diphtheria, tetanus toxoid, acellular pertussis, and inactivated, Sabin-derived polio vaccine | Tetravix, Quatrovax | D | Yes (November 2012) | |
2013 | November | 13-Valent conjugate pneumococcal | Prevenar 13 | D | Yes (November, 2013) |
[Table omitted. See PDF] |
Country (reference) | Vaccines recommended for all children in WHO position papers (except VZV) | |||||||||||
BCG | HBV | Polio | DTaP | Hib | PCV | RV | Measles | Rubella | Mumps | HPV | VZV* | |
Canada (31) | [white square] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] |
France (30) | [white up triangle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white square] | [white circle] | [white circle] | [white circle] | [white circle] | [white square] |
Germany (30) | [white square] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] |
Italy (30) | [white square] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white square] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] |
United Kingdom (30) | [white up triangle] | [white up triangle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white up triangle] |
United States (32) | [white square] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] | [white circle] |
Japan | [white circle] | [white up triangle] | [white circle] | [white circle] | [white circle]# | [white circle]# | [white square] | [white circle] | [white circle] | [white square] | [white circle]#,[dagger] | [white square]+ |
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