Elsevier

The Lancet

Volume 358, Issue 9284, 8 September 2001, Pages 791-795
The Lancet

Articles
Efficacy of single-dose SA 14–14–2 vaccine against Japanese encephalitis: a case control study

https://doi.org/10.1016/S0140-6736(01)05967-0Get rights and content

Summary

Background

In China, since 1989, an estimated 120 million children have been immunised with the SA 14–14–2 live-attenuated Japanese encephalitis (JE) vaccine at ages 1, 2, and 6 years. A case-control study of licensed vaccine found two doses to be 98% effective. Subsequently, researchers found that single-dose vaccine efficacy was high; we aimed to confirm this result.

Methods

During July 11–24, 1999, 160000 doses of JE vaccine were given to children aged 1–15 years, resident in three districts of Nepal. Several cases of JE were admitted to hospital from early August. We obtained names and addresses of cases with serological evidence of a recent infection from Bheri Zonal Hospital, Nepalgunj. We did a matched case-control study and calculated the odds ratio of vaccination among JE cases and age-sex matched village controls.

Findings

20 children, aged 1–15 years, were identified whose illness conformed with the JE case definition and were resident in villages receiving the vaccine. None of 20 JE cases had received JE vaccine compared with 326 of 557 age-sex matched village controls. The efficacy of a single dose of JE vaccine was 99·3% (CI 94·9–100 %).

Interpretation

A single dose of JE vaccine is highly efficacious in preventing Japanese encephalitis when administered only days or weeks before exposure to infection.

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)

  • J Ao et al.

    Selection of a better immunogenic and highly attenuated live vaccine strain of Japanese encephalitis II: safety and immunogenicity of live JBE vaccine SA 14–14–2 observed in inoculated children

    Chin J Microbiol Immunol

    (1983)
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