Population-based study of a free rubella-specific antibody testing and immunization campaign in Chiba city in response to the 2018–2019 nationwide rubella outbreak in Japan

ABSTRACT

Japan has not been able to eliminate rubella; as a result, the large rubella epidemic has occurred. Considering the complicated history of the vaccine policy in Japan, some susceptible populations became infected with rubella, resulting in an outbreak. We conducted a large serosurveillance against rubella in Chiba city after initiating free rubella-specific antibody testing and an immunization campaign during 2018–2019. The total number of rubella specific antibody tests that was conducted in the nationwide campaign and Chiba city original campaign was 8277 and 6104, respectively. The proportion of participants with an antibody titer of ≤1:16 using the hemagglutination inhibition (HI) test was higher in those in their 20–30s. On the contrary, the proportion of participants with an antibody titer of <1:8 using the HI test was higher in men in their 40–50s. This discrepancy possibly reflects the complicated history of the vaccine policy. The number of participants in the nationwide immunization campaign in this city was 1517, whereas that in the Chiba city campaign was 3607. The Chiba city campaign was effective against women in their 20–30s (child-bearing generation); however, the nationwide campaign was not sufficiently effective against men in their 40–50s because many workers were did not visit medical facilities to receive the measles–rubella vaccine.

KEYWORDS:

• Rubella
• measles–rubella vaccine
• serosurveillance
• rubella specific antibody testing
• immunization campaign
• Japan

Introduction

The rubella virus is a member of the Togaviridae family; it causes mild acute exanthematous viral infection in both children and adults. Its most critical clinical and public health problem is the incidence of stillbirth or severe birth defects known as congenital rubella syndrome (CRS), which occurs when the infection is present in the early stages of pregnancy. There is no specific treatment for rubella, but this disease is preventable by vaccination. The World Health Organization (WHO) recommended that all countries improve their rubella immunization programs and established a global rubella goal of eliminating measles and rubella in at least five WHO regions by the end of 2020.¹ In 2015, the WHO region of the Americans became the first in the world to be declared free of the endemic transmission of rubella.²

Japan has not eliminated rubella, and even now a large rubella epidemic is occurring. The national immunization program for rubella has changed over time, as shown in Table 1. As a result of the complicated vaccine policy history, some susceptible populations have become infected with rubella and caused various outbreaks. During 2012–2013, Japan had a large rubella outbreak involving more than 16,000 cases, including 45 cases of CRS.^3,4 The Ministry of Health, Labor and Welfare issued the Guidelines for the Prevention of Specific Infectious Diseases: Rubella in 2014, and the number of cases decreased. However, a second large rubella outbreak in the recent decade began in 2018, and more than 5,000 rubella cases including five CRS cases were confirmed.⁵ The epidemic primarily affected men in their 40s and 50s who had not received a rubella-containing vaccine (RCV). The government offered free rubella-specific antibody testing and free immunization with the measles–rubella (MR) vaccine in a campaign directed at men born between April 2, 1962 and April 1, 1979 who had not previously received an RCV; this 3-year campaign was initiated in February 2019 to eliminate rubella infection and CRS by 2022.⁶

Table 1. History of the national immunization program for rubella in Japan

Birth date	Vaccine	Schedule of national immunization program
		Men	Women
June 2, 2006–	MR-MR	Two doses(1^st dose: in childhood 2^nd dose: 1 year before entering elementary school)
Apr. 2,2000–June 1, 2006	Rubella-MR	Two doses(1^st dose: in childhood 2^nd dose: 1 year before entering elementary school)
Oct. 2, 1987–Apr. 1, 2000	Rubella*	One dose(individual vaccination in childhood)**
Apr. 2, 1979–Oct. 1, 1987	Rubella*	One dose(individual vaccination in junior high school students)
Apr. 2, 1962–Apr. 1,1979	Rubella*	None	One dose(group vaccination in junior high school students)
–Apr. 1, 1962		None

*The measles-mumps-rubella (MMR) vaccine was introduced in Apr. 1989; however, this vaccine was terminated in Mar. 1993 due to the adverse effect of aseptic meningitis.

** The measles-rubella (MR) catch-up immunization campaign was designed in 2008 to be conducted for five years to give an additional dose of the MR vaccine to children born from April 2, 1990 to April 1, 2000.

Chiba city is a regional central city with a population of approximately 980,000; it is located to the east of Tokyo. The rubella epidemic is also present in this city.⁷ In April 2014, the city government initiated an original rubella campaign for free rubella-specific antibody testing for women living in this city who wanted to become pregnant. In October 2018, the target was expanded to husbands of pregnant women or women who wanted to become pregnant. Furthermore, in April 2019, family members of these women were eligible for the campaign. Not only antibody testing but also the subsidization of MR vaccines was also initiated in November 2018 for all citizens who did not have sufficient rubella-specific antibodies.⁸

Two different campaigns for rubella elimination (Chiba city original campaign and nationwide campaign) were performed in this city, and each of those campaigns performed rubella-specific antibody testing. Little is known about the seroprevalence against rubella in the Japanese people, particularly stratified by sex and age. We conducted a large serosurveillance study of rubella in people who participated in these two campaigns in this city and considered the problem of the rubella epidemic in Japan.

Patients and methods

Study design

This prospective population-based study was conducted from October 2018 to November 2019 in Chiba city. We collected all registration sheets completed by every person who had lived in Chiba city and had received rubella-specific antibody testing or MR vaccines through the Chiba city campaign or nationwide campaign during this study period. We analyzed the data from the Chiba city campaign with the sheets collected from October 2018 to November 2019. We also analyzed the data from the nationwide campaign with the sheets collected from June 2019 to November 2019 because the nationwide campaign had begun in June 2019 in Chiba city. Rubella-specific serum antibody testing was assayed at commercial clinical laboratories using several approved kits. The assay methods and their usage rates are described in Table S1. Most laboratories performed the hemagglutination inhibition (HI) test or determined the enzyme immunoassay (EIA) value. The criterion for the recommendation of receiving MR vaccines was defined as ≤1:16 according to the HI test or <8 according to the EIA value in the Chiba city campaign. Conversely, this criterion was defined as ≤1:8 according to the HI test or <6 according to the EIA value in the nationwide campaign. We converted each titer into HI values using the kits explained in Table S1 and evaluated the seroprevalence using three different cutoff values (≤1:16, ≤1:8, and <1:8). In addition, we calculated the seronegative proportions in the total participants, excluding those with missing data.

This study was a collaborative research effort with the Chiba city government and the Chiba City Medical Association. This study was approved by the research ethics committee of Medical Mycology Research Center, Chiba University (No. 18).

Two rubella campaigns

Nationwide campaign

The nationwide campaign was informed by mass media, and coupons for antibody testing were distributed through local governments to approximately 6.46 million men (born between April 2, 1972 and April 1, 1979) in 2019. Subsequently, similar coupons were distributed to approximately 5.7 million men (born between April 2, 1966 and April 1, 1972) in 2020 and to 3.19 million men (born between April 2, 1962 and April 1, 1966) in 2021. Men who received a coupon could visit a clinic, complete the registration sheet, and receive the testing. If they did not have sufficient rubella-specific antibody titers (HI ≤ 1:8), they could receive one dose of the MR vaccine.

Chiba city campaign

The Chiba city campaign was advertised on the Chiba city magazine and website. Women who wished to become pregnant and the husbands or families of pregnant women or women who wished to become pregnant were eligible to participate in the antibody testing campaign. They could visit a clinic in the city, complete the registration sheet, and receive an antibody test for free. If the person had a negative rubella-specific antibody result (HI ≤ 1:16), irrespective of whether they were participating in the Chiba city campaign, he/she could receive one dose of the MR vaccine for free.

A comparison of the two campaigns is shown in Table 2.

Table 2. Epidemiology in Japan and Chiba city and comparison of the nationwide campaign and Chiba city campaign

	Japan	Chiba city
Population (Sep.30, 2019)	126,167,000	972,500
Men born between April 2, 1962 and April 1, 1979	12,160,000	138,800
Number of rubella infections (2019)	2,306	48
Number of CRS cases (2019)	4	0
Summary of campaign	Nationwide campaign	Chiba city campaign
Rubella-specific antibody testing
Target of this campaign	Men born between April 2, 1962 and April 1, 1979	Citizens who ●・want to become pregnant ●・are husbands or families of pregnant women or women who want to become pregnant
Subsidizing rate	100% free	100% free
Start date	April 2019 (June 2019 in Chiba city)	●・April 2014 (women wanting to become pregnant) ●・October 2018 (their husbands) ●・April 2019 (their families)
Measles–rubella vaccination
Target of this campaign	People who received the antibody campaign and did not have sufficient rubella specific antibodies	Citizens who did not have sufficient rubella-specific antibodies (regardless of whether the results were obtained through the Chiba city campaign)
Subsidizing rate	100% free	100% free
Start date	April 2019 (June 2019 in Chiba city)	November 2018

CRS, Congenital rubella syndrome

Results

Rubella-specific antibody testing

Table 3 shows the seroprevalence of rubella-specific antibodies from the nationwide campaign data. There were 8,277 total participants (8,273 with serological data) over six months. The seronegative proportions according to the HI test results with titers of ≤1:16, ≤1:8, and <1:8 were 30.1%, 23.5%, and 14.6%, respectively. Table 4 shows the seroprevalence of rubella-specific antibodies based on the Chiba city campaign data classified by sex and age. There were 6,104 participants (6,103 with characteristic data) over 14 months. The overall seronegative proportions according to HI test results with titers of ≤1:16, ≤1:8, and <1:8 were 33.9%, 19.7%, and 9.4%, respectively. Figure 1 shows the seronegative proportions from both the campaigns evaluated at three different titer cutoff values and stratified by age and sex. The seronegative proportions were higher in young people, particularly those in their 20s, when using the ≤1:16 HI test cutoff value; however, the seronegative proportion was higher in men in their 40s and 50s when using the <1:8 cutoff value.

Table 3. Seroprevalence of rubella-specific antibodies from the nationwide campaign data

		n (%)
	Number of participants	HI < 1:8	HI ≤ 1:8	HI ≤ 1:16
Total	8273	1207 (14.6)	1944 (23.5)	2487 (30.1)

HI, hemagglutination inhibition test

Table 4. Seroprevalence of rubella-specific antibodies from the Chiba city campaign data classified according to sex and age

			n (%)
	Age (y.o.)	Number of participants	HI < 1:8	HI ≤ 1:8	HI ≤ 1:16
Total		6103	572 (9.4)	1202 (19.7)	2067 (33.9)
Men	Total	3256	399 (12.3)	735 (22.6)	1130 (34.7)
	0–9	5	2 (40)	3 (60)	4 (80)
	10–19	3	1 (33.3)	1 (33.3)	2 (66.7)
	20–29	533	55 (10.3)	153 (28.7)	264 (49.5)
	30–39	1708	167 (9.8)	341 (20)	544 (31.9)
	40–49	726	131 (18)	180 (24.8)	243 (33.5)
	50–59	257	41 (16)	53 (20.6)	66 (25.7)
	60–69	15	1 (6.7)	3 (20)	4 (26.7)
	70–	9	1 (11.1)	1 (11.1)	3 (33.3)
Women	Total	2847	173 (6.1)	467 (16.4)	937 (32.9)
	0–9	12	2 (16.7)	5 (41.7)	8 (66.7)
	10–19	18	3 (16.7)	8 (44.4)	11 (61.1)
	20–29	887	59 (6.7)	177 (20)	366 (41.3)
	30–39	1421	90 (6.3)	227 (16)	435 (30.6)
	40–49	374	9 (2.4)	26 (7)	80 (21.4)
	50–59	88	5 (5.7)	13 (14.8)	22 (25)
	60–69	38	4 (10.5)	9 (23.7)	13 (34.2)
	70–	9	1 (11.1)	2 (22.2)	2 (22.2)

y.o, years old; HI, hemagglutination inhibition test

Figure 1. The seronegative proportions from both campaigns evaluated at three different titer cutoff values and stratified based on age and sex

Each black, striped, and white bar indicates the percentage of participants whose rubella-specific antibody titers were <1:8, = 1:8, and = 1:16 according to the HI test results, respectively. The seronegative proportions were higher in young people, particularly those in their 20s, according to an HI ≤ 1:16 cutoff value (men: 49.5%, women: 41.3%); however, the seronegative proportions were higher in men in their 40s and 50s when an HI cutoff value of <1:8 was used (14.8% and 16.0%, respectively). y.o, years old; HI, hemagglutination inhibition test.

Rubella vaccinations

Tables 5 and 6 show the numbers of people who had received MR vaccines in the nationwide campaign (Table 5) and those in the Chiba city campaign stratified by age and sex (Table 6). In the nationwide campaign, the 1,517 participants represented 2.4% of the total population of the target age during the study period (men born between April 2, 1972 and April 1, 1979) in Chiba city. The Chiba city campaign involved 3,607 participants (3,593 with characteristic data), and the ratio of men/women was 0.61. The most common participants were women in their 20s and 30s, who comprised the child-rearing generation.

Table 5. Number of people who had received the measles-rubella vaccine in the nationwide campaign and the vaccination rate of the total population of the target ages in Chiba city

	Number ofparticipants	Vaccination rate of the total populationof the target ages in Chiba city (%)*
Total	1517	2.4

* The number of men born between April 2, 1972 and April 1, 1979 in Chiba city as of September 30, 2019 (62,943 people).

Table 6. Number of people who had received the measles-rubella vaccine during the Chiba city campaign classified according to sex and age

	Age (y.o.)	Number ofparticipants
Total		3593
Men	Total	1368
	0–9	4
	10–19	11
	20–29	272
	30–39	495
	40–49	463
	50–59	91
	60–69	22
	70–	10
Women	Total	2225
	0–9	7
	10–19	73
	20–29	843
	30–39	1043
	40–49	171
	50–59	67
	60–69	18
	70–	3

y.o, years old

Visiting day of the week

Figure 2 illustrates the percentage of participants in the nationwide campaign who visited the medical facilities on each day of the week. We found that 20.7% of the participants in the antibody testing campaign and 34.8% of the participants in the MR vaccination campaigns visited the medical facilities on Saturday.

Figure 2. The percentage of participants in the nationwide campaign who visited medical facilities on each day of the week

The black bar indicates the percentage of participants who visited medical facilities on Saturdays (rubella-specific antibody testing: 20.7%, measles–rubella vaccination: 34.8%). The participants in the nationwide campaign tended to visit medical facilities on Saturdays.

Discussion

We investigated the seroprevalence of rubella-specific antibodies through two different rubella campaigns and identified low antibody levels of both men in their 40s and 50s and young people comprising the child-rearing generation. This study is valuable because it provides large-scale seroprevalence data by sex and age in Japan. Moreover, to our knowledge, this is the first population-based study conducted in Japan after the initiation of a nationwide campaign to combat the rubella epidemic in 2018–2019.

In Japan, a routine rubella immunization program was initiated for junior high school girls in August 1977 that consisted of one vaccination dose; it was expanded to boys in April 1995. A two-dose vaccination series of the MR vaccine was implemented in 2006 for young children, and a five-year catch-up immunization campaign was designed for adolescents. The current national immunization program includes two doses of the MR vaccine (the first dose is given at 1 year of age and the second dose is given 1 year before entering elementary school; typically aged 5 or 6 years). The 2018 vaccine coverage rates for the first and second doses of the MR vaccine were 98.5% and 94.6%, respectively.⁹ However, immunization for adults is insufficient because of the vaccine’s historical background. Therefore, 95% of rubella infections were occurring in adults.^6,10,11 Our seroprevalence study results support this epidemiology.

The nationwide campaign targeted men in their 40s and 50s who were born between April 2, 1962 and April 1, 1979. Our results indicated that approximately 20% of participants had rubella-specific antibody titers ≤1:8 according to the HI test results and thus required the MR vaccine. National epidemiological surveillance in 2016 had reported almost the same seronegative proportion in this generation.¹² Our result also indicated that the proportions of men in their 40s and 50s with antibody titers <1:8 according to the HI test were higher than those in other age groups. Consequently, this “non-vaccinated generation” was presumed to be susceptible to rubella and thus the cause of the nationwide epidemic. A nationwide campaign can encourage such individuals to receive MR vaccines and rectify their insufficient immunity against rubella. Interestingly, proportion of participant in this age range with antibody titers ≤1:16 using the HI test were not higher than those of the younger generations. This difference may be because this “non-vaccinated generation” mainly contained rubella-naive individuals and rubella-affected individuals.

Chiba city is unique in conducting an original rubella campaign for women who want to become pregnant and their families in addition to the nationwide rubella campaign for men in their 40s and 50s. The main purpose of the former campaign is the direct prevention of CRS. We were able to identify the seroprevalence of rubella-specific antibody titers by sex and age groups through this campaign. Our study reported seronegative proportions of approximately 40–50% in individuals in their 20s and 30s for titers ≤1:16 according to the HI test, which is higher than that reported in some previous Japanese studies.^13,14 The target of our study was the general public and not pregnant women or health care workers. This might have caused selection bias; however, the number of rubella infections and the number of routine MR vaccinations in this city were not particularly different from those in other cities. One report in 2018 highlighted insufficient specific antibody levels and susceptibility to rubella infection in Japanese young people.¹⁵ Our results suggested the presence of low antibody levels against rubella in recent Japanese young people and supported this previous report. We supposed there were two reasons why these young people had low antibody levels against rubella. One reason is the decrease of natural exposure to the rubella virus. Since the introduction of universal immunization campaign, the incidence of rubella infection has decreased in Japan even though rubella epidemics have repeatedly occurred, and young people have rarely encountered the natural rubella virus.¹⁶ A recent study in Ireland reported increased rubella susceptibility of antenatal women and suggested that the waning of rubella antibody levels was in part due to the absence of circulating wild-type rubella virus in the community.¹⁷ The other reason is insufficient immunization of this generation. Although most people in this generation had received RCV at least once, possibly explaining the low proportion of antibody titer of <1:8 using HI test, people in their 30s had not received the second dose of RCV because the two-dose MR vaccination program was not initiated in their childhood. People in their 20s had a chance to receive the MR vaccination program during their adolescent period; however, their vaccine coverage rates were low.^6,18

Therefore, our result clearly indicates the importance of the Chiba city campaign and the necessity of additional policies for this child-rearing generation.

In the early stage of the nationwide campaign, fewer people received the MR vaccine in Chiba city than expected. The vaccination rate (2.4%) was lower than the 10.8% achievement line set by the Ministry of Health, Labor and Welfare (the estimated number of participants in 2019 based on past serological data, i.e., 700,000, divided by the total population of the target ages in 2019, i.e., 6,460,000), and this result was also slightly lower than the 2.7% that other prefectures averaged.¹⁹ The nationwide campaign did not progress well potentially because many workers were unable to find time to visit medical facilities. For a person to receive the MR vaccine using this campaign, he had to visit the clinic at least twice (antibody testing and vaccination were performed on separate visits). We found that 34.8% of participants visited medical facilities on Saturdays, as shown in Figure 2. It was difficult for adults who worked on weekdays to visit the medical facilities several times. This problem was also evident in other areas in Japan. For example, the Tokyo Metropolitan Government had been promoting a project to prevent rubella and other infectious diseases in workplaces, and some companies decided to organize group vaccinations at their offices.^20,21

It was difficult to evaluate the vaccination rate in the Chiba city campaign because we could not estimate the population that was aiming to become pregnant. However, we discovered that the number of vaccination participants (subjects who received the vaccine during the campaign) was higher than that of seronegative people based on the Chiba city campaign results, and most of the vaccination participants were women of the child-bearing age. According to our additional investigation, they had undergone antibody testing during a routine prenatal checkup, and they had then received the vaccine through the Chiba city campaign after giving birth in the same maternity clinic. Hisano et al. reported the effectiveness of MR vaccination for mothers in the early puerperal phase.²² Our results indicated that the Chiba city campaign contributed to the increase in the number of MR vaccinations in child-rearing women, who are the primary group requiring protection against rubella infections.

There are some limitations in this study. Firstly, this study used local data and did not consider the regional differences in Japan. Moreover, this study used interim data because the Chiba city campaign had started before this study began and both campaigns are still ongoing. Further larger and longer studies are necessary. Second, this study only used the data obtained from people who voluntarily participated in these campaigns. As a result, the serosurveillance results could not reflect people who were not interested in these campaigns or those who undertook antibody tests outside these campaigns, for example, those who used the medical insurance and who undertook workers’ checkups. Finally, neither campaign could link together both antibody testing and MR vaccination to the individual, and thus we were unable to determine how many participants received the MR vaccine as a result of antibody testing. However, these data are the results of a population-based study, and we believe that they are worth reporting.

In conclusion, we conducted a large serosurveillance study on rubella in people who participated in two campaigns in Chiba city and found that the proportion of participants with an antibody titer of ≤1:16 using the HI test was higher among people in their 20–30s; however, the proportion of participants with an antibody titer of <1:8 using the HI test was higher in men in their 40–50s. This discrepancy possibly reflects the complicated history of the vaccine policy. The Chiba city campaign was effective in women in their 20s and 30s, which is particularly important because they comprise the child-rearing generation; however, the nationwide campaign was not sufficiently effective in men in their 40s and 50s because many workers did not visit medical facilities to receive MR vaccines. We hope this study can be used to promote these campaigns.

Disclosure of potential conflicts of interest

All authors reported no potential conflicts of interest.

Acknowledgments

We thank all the participants in these campaigns and the clinics and public health centers who were associated with this study.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website

Additional information

Funding

This work was supported in part by the joint research funding with Chiba city in 2019 and joint research funding shared with the Medical Mycology Research Center, Chiba University in 2020 (Accepted No. 20-27).