ArticlesEfficacy of single-dose SA 14–14–2 vaccine against Japanese encephalitis: a case control study
Introduction
Japanese encephalitis (JE), caused by a mosquito-borne flavivirus transmitted in Asia, is a serious disease of children in the region, accounting for more than 35000 reported cases and 10000 deaths annually.1 In the past 25 years, transmission has intensified in certain countries and the disease has extended its geographical range to previously unaffected areas of Asia and to northern Australia.1, 2, 3, 4, 5 There is no effective or specific treatment for JE, which has a case fatality of 20–40% and produces residual neurological or psychiatric sequelae in 25–40% of survivors. Most authorities agree that the control of JE requires universal childhood immunisation, because 70% of reported cases occur in children and mosquito vectors breed in rice paddies, making vector control virtually impossible.5 A widely available inactivated vaccine, produced from infected mouse brain tissue, is expensive and requires two or three doses to achieve protective efficacy and, in practice, further booster doses to maintain immunity.6, 7 Neurological, allergic, and serum sickness-like reactions have been reported following one or more doses of this vaccine.2, 7, 8
A live-attenuated JE (SA 14–14–2) vaccine developed in China was licensed in 1988.9 Since then, an estimated 120 million children have been immunised with this vaccine with no adverse events reported in several large studies.9, 10, 11, 12 In one study,9 healthy Chinese children resident in JE non-endemic areas were randomised into three groups. 48 were vaccinated with SA 14–14–2, while 49 and 48 others were given SA 14–5–3 live-attenuated strain or inactivated JE vaccine, respectively. No adverse events or differences were seen between the groups. In a larger 1987 study,11 four doses of live-attenuated vaccine were given to 588512 healthy children resident in Yunnan Province, China. Adverse events were reported passively from the whole cohort. A subgroup of 867 children, aged 1–6 years, were closely monitored for three weeks.11 Only minor local reactions were noted. In another study,12 block randomised cohorts of 13266 vaccinated and 12951 unvaccinated 1–2-year-old children were followed prospectively for 30 days: no neurological events were detected and the incidence of minor symptoms and allergic reactions in vaccinees was identical to that in controls.
In China, SA 14–14–2 vaccine is given in a three-dose series to children at ages 1, 2, and 6 years during a large campaign in the spring. Protective effectiveness of two doses was measured as 98% in one case-control study.13 The effectiveness of a single dose was 80% (95% CI 44–93%), a measurement that was underpowered due to the small number of JE cases receiving only one dose of vaccine. In other reported studies, a single dose of this vaccine has been shown consistently to result in a high seroconversion rate.9, 11, 14, 15
It seemed possible that SA 14–14–2, like yellow fever 17D, may provide long-term protection following a single dose. However, evidence from formal efficacy studies is required. Efficacy can most easily be measured in a largely unimmunised population. Beginning in mid-July 1999, about 160000 doses of SA 14–14–2 were given to high risk Nepalese children, aged 1–15 years, living in the Terai region. A very large JE epidemic occurred immediately thereafter. We did a matched case-control study to measure the effectiveness of a single dose of JE vaccine in this population at high risk of JE.
Section snippets
Study area
Nepal is a landlocked mountainous country with a population of 22 million, situated on the southern slopes of the Himalayan range between China in the north and India in the south, east, and west (figure). Nepal has mountains, inner Terai valleys, and outer Terai foothills and plains with tropical and subtropical climate. Monsoon rains support intensive agriculture, including rice growing, on the Terai plains, home to 11·5 million people. Rice paddies support the breeding of Culex
Results
A large epidemic of JE occurred in Nepal in 1999, peaking during the months of August and September. As in previous years, a few cases were reported first in April and May, but in late July the epidemic curve began to rise, peaking the week of Aug 30. 2924 cases and 434 deaths (15% case fatality) of acute encephalitis were reported to the EDCD of the Ministry of Health, Nepal. Of the cases, 2083 (77%) were reported from two districts: 1041 cases from Kailali and 1042 from Banke (figure),
Discussion
There were several reasons why it was inappropriate to assess protective efficacy of SA 14–14–2 vaccine using a cohort study. Neither manpower nor funds nor time were available to establish an unvaccinated cohort. Because attack rates of JE are low, in order to have sufficient power, very large cohorts would have been required to measure efficacy. As SA 14–14–2 vaccine is a licensed vaccine of proven high effectiveness, we considered administration of a placebo unethical. Under the
References (23)
New initiatives for the control of Japanese encephalitis by vaccination
Vaccine
(2000)- et al.
Adverse events after Japanese encephalitis vaccination: review of post-marketing surveillance data from Japan and the United States
Vaccine
(2000) - et al.
Effectiveness of live-attenuated Japanese encephalitis vaccine (SA 14–14–2): a case-control study
Lancet
(1996) - et al.
Primary and booster immune responses to SA14–14–2 Japanese encephalitis vaccine in Korean infants
Vaccine
(1999) - et al.
Japanese encephalitis vaccines
- et al.
Dengue (with notes on yellow fever and Japanese encephalitis)
- et al.
The epidemiology of Japanese encephalitis: prospects for prevention
Epidemiol Rev
(1992) - et al.
Protection against Japanese encephalitis by inactivated vaccines
N Engl J Med
(1988) Japanese encephalitis: inactivated Japanese encephalitis virus vaccine
MMWR
(1993)