Milestones in history of adult vaccination in Korea.

Vaccination is one of the most effective and cost-benefit interventions that reduced the mortality. Major vaccine preventable diseases have decreased dramatically after the introduction of immunization program in Korea. In this article, we review milestones in history of immunization program, especially in adult vaccination.

Introduction

The impact of vaccination on the health of people is hard to exaggerate. With exception of safe water, no other modality has had such an enormous effect on the mortality reduction. Table 1 shows that major vaccine preventable diseases have decreased dramatically after the introduction of immunization program in Korea. Previous studies reviewed history of national immunization program [1,2] and immunization policies in Republic of Korea [1,3]. In this article, we update milestones in history of immunization (Table 2), and review adult vaccination in Korea.

Table 1

Impact of immunization on the incidence of major vaccine preventable diseases in Korea

a)In 2001, 32,647 cases of measles reported because of a measles epidemic between January 2000 and July 2001.

b)Rubella became reportable disease since 2000.

Table 2

Milestones in history of immunization in Korea

BCG, Bacillus Calmette-Guérin; DPT, diphtheria, pertussis, tetanus; MMR, measles-mumps-rubella; MR, measles-rubella; WHO, World Health Organization; Td, tetanus and diphtheria toxoid; OPV, oral polio vaccine; IPV, inactivated polio vaccine; FDA, Food and Drug Administration; HepB, hepatitis B; DTaP, diphtheria, tetanus, acellular pertussis; Tdap, tetanus, reduced diphtheria, acellular pertussis; JEV, Japanese encephalitis virus.

Source: adapted and modified from Korea Centers for Disease Control and Prevention [3].

Brief History of Adult Vaccination in Korea

Smallpox

The first vaccination in Korea was against smallpox. In 1790, Jaega Park brought a book on smallpox vaccination from China. In 1780, he was successful in inoculation of "smallpox vaccine," which was made of crusts from smallpox patients. In 1835, Yakyong Jung inoculated vaccines taken from lesions of cowpox. But he kept it secret and did not practice widely [4]. It was Seokyong Jee who introduced smallpox vaccination and opened a vaccine production site in Seoul in 1880. It was 1882 when provincial governments began to establish offices for smallpox vaccination campaign, which was the first national immunization program in Korea [5].

In 1912, the government established Department of Hygiene, and Division of Bacteriology was responsible for the production of smallpox vaccine. In 1954, Contagious Disease Prevention Act was legislated, and the Law designated 8 communicable diseases to be included into the National Immunization Program. With the help of smallpox vaccination campaign, the number of smallpox cases had decreased dramatically year by year, and the last case was reported in 1961. Finally, smallpox vaccination was discontinued in 1979, one year before the declaration of smallpox eradication by World Health Organization.

As number of susceptible persons accumulated after the discontinuation of smallpox vaccination, some experts raised concern that smallpox virus might be used as a potential biological weapon. This concern was heightened in 2001 when the event of anthrax bioterrorism occurred soon after the 911 attack of World Trade Center in the USA. To be better prepared for bioterrorism, the government stockpiled a first-generation vaccine (Lancy-Vaxina) purchased from a Swiss pharmaceutical company. We conducted a single-blind, randomized trial of 2 dilutions (1:1 or 1:10) of Lancy-Vaxina vaccine [6]. The results of the study showed that a 1:10 dilution of the vaccine can be successfully given to the vaccine naïve and previously vaccinated persons.

To avoid unwanted immune responses to calf-derived material and to prevent bovine prion transmission, a cell-culture derived smallpox vaccine (CJ-50300) was developed by a Korean pharmaceutical company. A randomized, double-blind, controlled clinical trial demonstrated that CJ-50300 effectively evoked a cutaneous take reaction, and was not associated with any serious adverse reaction [7]. The vaccine has been licensed by Korea Food and Drug Administration in 2008.

Hemorrhagic fever with renal syndrome

The etiologic agent of hemorrhagic fever with renal syndrome (HFRS) was identified by Lee et al. [8] in 1978, and the etiologic agent, Hantaan virus, was successfully propagated in a cell line of human origin in 1983 [9]. In 1988, Lee and Ahn [10] reported that an inactivated Hantaan virus vaccine was developed. The seed virus for the vaccine, ROK84-105-1, was isolated from blood of a HFRS patient directly in Vero E6 cell culture. The virus was passaged 3 times in the brain of ICR suckling mice to increase virus yield. Then, pool of 5% suspension of suckling mice brain in phosphate buffered saline was inactivated with 0.05% formalin. This inactivated vaccine, named Hantavax, was the world's first HFRS vaccine. It got approved in 1990 under the condition of further clinical trials.

A field trial of Hantavax was conducted in HFRS endemic areas in Yugoslavia from 1996 to 1998 [11]. Three thousand and nine hundred people living in the endemic areas were randomized into placebo or vaccination group, and followed for 2 years to monitor HFRS development. The researchers reported that they found no HFRS case among 1,900 vaccinees, whereas they confirmed 20 HFRS cases among 2,000 non-vaccinated controls. Any remarkable local or systemic side effects were not reported in the study.

Park et al. [12] conducted a case-control study to evaluate the protective effectiveness of Hantavax. This study enrolled 57 soldiers with HFRS as cases, and matched controls were selected among the other patients at the same military hospital where the case patient had been admitted. They suggested that effectiveness increased as the number of doses increased: 25% for one dose, 46% for two doses, and 75% for three doses. However, all 95% confidence intervals overlapped zero; therefore, the findings could be due to mere chance [12].

The immunological response to Hantavax was evaluated in human volunteers in several studies [13-19]. Table 3 summarizes the results of the clinical trials. Because the seroconversion rate is low with single dose of Hantavax, a two dose series of primary vaccination is recommended. As shown in Table 3, seroconversion rates were greater than 90% after 2 doses of primary vaccination. In contrast, Sohn et al. [17] reported that neutralizing antibody responses were suboptimal, and they suggested the vaccine should be improved to produce a higher protective immune response. Some authors suggested that booster vaccination is necessary at 1 year after the primary vaccination [16,19]. However, it is not known which immunological parameters are correlated with the protective immunity against HFRS. Well-designed field trials are warranted to resolve the issues surrounding the efficacy and persistency of protective immunity conferred by Hantavax.

Table 3

Summary of immunological response to Hantavax in clinical trials reported in the literature

Values are presented as number (%).

IFA, immunofluorescent assay; ELISA, enzyme-linked immunosorbant assay; HDPA, high density particle agglutination; PRNT, plaque reduction neutralizing antibody test.

Source: adapted from Shon JW, Kim HY. Hantaan virus. In: Korean Society of Infectious Diseases, editor. Vaccination for adult. 2nd ed. Seoul: MIP; 2012.

Leptospirosis

In early 1980s, outbreaks of hemorrhagic pneumonia occurred among farmers working in rice paddy. The etiology of the outbreaks was identified as leptospirosis. Most of the isolates were Leptospira icterohemorrhagiae serovar lai. L. icterohaemorrhagiae strain HY-10 [20], isolated from a patient in Yeoju, Gyeonggi Province, was used to develop an inactivated vaccine. Korea National Institute of Health conducted studies on immunogenicity and safety of the candidate vaccine between 1985 and 1987. The seroconversion rate was 80.8%, and serious side effect was not reported. The protective efficacy of the vaccine was not evaluated [21].

The government introduced immunization against leptospiroris as a supplementary immunization activity in 1988. A 2 dose series of vaccination, with 7-10 days interval, was recommended during April and May, before the rainy season in Korea. Domestic pharmaceutical companies (Green Cross, Boryong, Hankook Vaccine, CJ Pharmaceutical, and SK Chemical) produced inactivated vaccines. The vaccines were inoculated to 200,106 persons in 1988, 145,276 persons in 1989, 283,616 persons in 1990, 541,300 persons in 1991, 825,104 persons in 1992, 780,579 persons in 1993, and 490,608 persons in 1994.

The immunization activity was discontinued in late 1997, because of the following reasons: 1) booster vaccination was required every 6 months as the vaccine-induced antibody waned rapidly; 2) serotypes of leptospira might vary according to the geographic areas, previous vaccination, and animal reservoirs; 3) alternative preventive measures, such as chemoprophyaxis, early detection and treatment, education for exposure reduction, were more cost-effective than vaccination; 4) the incidence of leptospirosis decreased dramatically in 1990s.

Influenza

Seasonal influenza

Vaccination against seasonal influenza was introduced as a supplementary immunization activity in 1997. Persons who had high-risk conditions for complication of influenza were recommended annual influenza vaccination. The high-risk groups included persons of 6 months of age or older who had 1) lung or heart diseases; 2) chronic illness residing nursing facilities; 3) chronic illness requiring regular clinic visit, such as metabolic disease (diabetes mellitus), renal disease, chronic liver disease, malignancy, immunocompromised conditions, hemoglobinopathy, and children of 6 months to 18 years of age taking aspirin; 4) persons of 65 years of age and older; 5) healthcare workers and family member of patients. The high-risk groups were expanded to include pregnant women and persons of 50 to 64 years old in 2003; children 6-23 months old, farmers working at chicken, pig, and duck farm and primary responders to avian influenza in 2004 [22]. In 2010, after the outbreak of 2009 pandemic influenza, children of 24 to 59 months of age and persons with neuromuscular diseases were also included. Among high-risk groups, vaccine coverage rates in 2006 were estimated 56% in children and 64% in adults.

2009 Pandemic influenza A (H1N1)

The first case of 2009 pandemic influenza A (H1N1) was identified on 1 May 2009 in Republic of Korea. The pandemic influenza peaked in late October (44th week) 2009. A total of 763,759 cases were reported and 270 patients died of the pandemic influenza [23].

An inactivated, split vaccine against 2009 influenza A (H1N1), GreenFlu S, was developed by a domestic pharmaceutical company (Green Cross Cooperation). The vaccine was produced in embryonated chicken eggs. A prospective, open-label, multicenter clinical trial was conductive to evaluate safety and immunogenicity of the vaccine [24]. The study enrolled 251 healthy Korean children from 6 months to <18 years of age. The vaccine contained 7.5 µg (for children <3 years of age) or 15.0 µg (children 3 to <18 years of age) of hemagglutinin antigen per dose. Twenty one day after 2-dose series of vaccination, hemagglutinin inhibition titers of 1:40 or greater was observed in 55.9% of children 6 months to <3 years of age, 69.5% of children 3 years to <9 years of age, and 90.5% of subjects 9 years to <18 years of age. No serious adverse reaction was observed [24]. The vaccine was licensed on 21 October 2009 by Korea Food and Drug Administration. MF59-adjuvanted vaccine, GreenFlu S Plus, was also developed and evaluated in a clinical trial [25].

Korea Centers for Disease Control and Prevention (KCDC) launched a vaccination campaign against 2009 pandemic influenza on 27 October 2009. The government purchased 25 million doses of GreenFlu S and GreenFlu S Plus to cover high risk groups. A total of 12,996,983 persons (26% of population) were vaccinated. Of those vaccinated, 95.8% were from high priority groups that included health care workers, students attending elementary, junior and high schools, children 6 months to 6 years of age, pregnant women, military personnel, persons living in welfare facilities, persons with chronic medical conditions, and elderly people of 65 years or older. Of 22,901,461 persons of the high priority groups, 54.4% were vaccinated [26]. Table 4 summarizes the coverage rate of vaccination against 2009 pandemic influenza.

Table 4

Vaccination coverage rate for pandemic influenza A (H1N1) 2009 in Korea

Source: adapted from Lee et al. [26].

Adult Vaccination Program in Korea

In 2006, KCDC recommended several vaccinations for adults [3]. The recommended vaccinations included vaccinations against influenza for persons of 50 years or older; pneumococcal infection for 65 years or older; hepatitis B, measles-mumps-rubella (MMR), tetanus and diphtheria toxoid (Td) and varicella for all adults who are susceptible to the infections. It also recommended hepatitis B virus, influenza, MMR and varicella vaccinations for healthcare workers. In 2007, Korean Society of Infectious Diseases (KSID) published a textbook on adult immunization, titled 'Vaccination for Adult.' In 2012, KSID published second edition of the book, and revised its previous recommendation on adult immunization. Fig. 1 shows the recommended adult immunization schedule by KSID. List of vaccines licensed by Korea Food and Drug Administration is shown in Table 5.

Fig. 1

Adult immunization schedule 2012, recommended by the Korean Society of Infectious Diseases.

Td, tetanus and diphtheria toxoid; Tdap, tetanus, reduced diphtheria, acellular pertussis; HBsAb, hepatitis B surface antibody; IgG, immunoglobulin G.

a)Hepatitis A (high-risk group): persons with chronic liver disease; persons working at child-care facilities; medical personnel and laboratory workers with potential risk of exposure to hepatitis A virus; food handlers working at restaurants; persons traveling to or working in countries where hepatitis A is endemic; persons who receive blood products frequently; men sex with men; IV drug users; persons who contact with acute hepatitis A patients within 2 wk.

b)Hepatitis B (high-risk group): men sex with men; sexually active persons with more than one partner; human immunodeficiency virus (HIV) patients; IV drug users; household contacts and sexual partners of persons with hepatitis B virus (HBV) carrier; patients with chronic renal failure; patients with chronic liver disease; workers who are frequently exposed to HBV; clients and staff members of institutions for persons with developmental disabilities.

c)Measles-mumps-rubella (vaccination recommended for high-risk group): Although serological test (especially, for measles) can be done for laboratory evidence of immunity, vaccination without serologic test would be cost saving. High-risk group: healthcare personnel (serological test required, 2 doses); persons traveling to developing countries; family member who take care of immunocompromised patient; students who dwell in dormitory.

d)Varicella: vaccination recommended for high-risk group if serological test reveal no evidence of immunity. High-risk group: healthcare worker; family contacts of immunocompromised patients; teachers and child-care employees; students; military personnel; residents of correctional institutions; non-pregnant women with expecting pregnancy; adolescent and adult living in households with children; international travelers.

e)Meningococcal (high-risk group): persons with anatomical or functional asplenia; persons with complement component deficiencies; military personnel; (especially for recruits); laboratory workers exposed to meningococcus; persons who travel or live in an endemic area, particularly if their contact with local populations will be prolonged; college students living in dormitories. 2 dose series is recommended for adults with anatomical or functional asplenia, complement component deficiency, HIV infection; 2 doses should be administered at 0 and 2 mo. Revaccination with meningococcal conjugate vaccine every 5 yr for adults who remain at increased risk for infection.

f)Pneumococcal (high-risk group): chronic lung disease (including asthma); chronic cardiovascular disease; diabetes; chronic liver disease; chronic renal failure; nephrotic syndrome; functional or anatomical asplenia; immunocompromised patients (congenital immunodeficiency, HIV infection; leukemia, lymphoma, Hodgkin's disease, multiple myeloma, other malignancy; solid organ transplantation), (vaccinate with 3 or 4 doses of protein conjugate vaccine for hematopoietic stem cell transplants); prolonged use of high-dose corticosteroids or immunosuppressive agents; cochlear implant. One-time revaccination is recommended for persons aged 65 years or older if they were vaccinated 5 or more years previously and they were less than 65 years of age at the time of primary vaccination. One-time revaccination after 5 years is recommended for patients with chronic renal failure, nephrotic syndrome, functional or anatomical asplenia, immunocompromised conditions, prolonged use of immunosuppressive agents.

Source: adapted from Korean Society of Infectious Diseases. Vaccination for adult. 2nd ed. Seoul: MIP; 2012.

Table 5

List of vaccines licensed by Korea Food and Drug Administration, as of April, 2012

HA, hematogglutinin; MMR, measles-mumps-rubella; BCG, Bacillus Calmette-Guérin; DTwP, diphtheria, tetanus, and whole-cell pertussis; HepB, hepatitis B; Hib, haemophilus influenzae type b; IPV, inactivated polio vaccine.

Source: from website for Korea Food and Drug Administration. Accessed on 5 July 2012 (Visit http://www.kfda.go.kr/index.kfda?searchkey=title:contents&mid=70&searchword=백신&cd=&pageNo=1&seq=12836&cmd=v).

Adult immunization has become increasingly important for the following reasons: incomplete childhood immunization, waning immunity over time (e.g., diphtheria-pertussis-tetanus), changing epidemiology of some infectious diseases (e.g., hepatitis A virus), increase in overseas travel to endemic areas (e.g., meningococcal meningitis and yellow fever), introduction of newly developed vaccines (e.g., human papillomavirus and zoster vaccines), and increase in elderly persons and immunocompromised patients [27]. Although immunization has become a routine pediatric practice, it has not been as well integrated into routine clinic visits for adults. Besides influenza vaccine, most adult vaccines are severely under-utilized in Republic of Korea. A recent study reported the pneumococcal vaccination rate was less than 1% among elderly 65 years or older [28]. To raise coverage rate, multiple efforts including burden of disease study for vaccine preventable diseases, cost-benefit analysis for vaccination, education of physicians, and advertisement for adult vaccination are needed.