1 INTRODUCTION

Japanese encephalitis (JE) is mostly a childhood disease. South, Southeast, and East Asia residents are at higher risk, along with visitors to the JE endemic areas. The fatality is 20%−30% and over 30%−50% of the JE recovered individuals have persisting sequelae, mostly neuropsychiatric.^{1, 2} The disease inflicts a significant socioeconomic and public health burden. Treatment is mostly supportive and symptomatic.³

The areas endemic to JE are recommended to implement the JE vaccine in national immunization programs even if JE cases are low.⁴ As animal reservoirs involve multiple hosts, the elimination of the JE virus is very difficult. Therefore, vaccination is considered an effective preventive measure. The efficacy of the live-attenuated SA 14-14-2 JE vaccine is reported between 80% and 99% following partial vaccination and over 98% with complete vaccination. However, the incidence of JE continues despite vaccination in supplemental campaigns and routine immunization schedules.^{5, 6}

The JE among children is a major public health problem in central India.^{6, 7} After 2006, JE endemic districts were prioritized for the implementation of JE vaccination in Maharashtra and Telangana states. Initially, JE vaccination was introduced in campaign mode using a single dose among 1−15 years children along with recommended surveillance standards.^{7, 8} The routine immunization schedule, for the protection of susceptible birth cohorts, includes two doses of live-attenuated SA 14-14-2 JE vaccine—first at 9−12 and second at 16−24 months.⁹ Since October 2013, the JE endemic areas have implemented a two-dose schedule, administered with the measles-rubella (MR) vaccine.

Acute encephalitis syndrome (AES) cases are reported year-round from endemic districts of Maharashtra and Telangana states. An increase in JE cases despite JE vaccination raises concerns regarding the adequacy of JE vaccination uptake in medium-endemic central India. Therefore, in an attempt to explain the reasons for the continued occurrence of JE and AES in central India, we aimed to estimate JE vaccination coverage, as one of the most important factors, achieved in routine immunization schedules in Maharashtra and Telangana states in central India.

2 METHODS

2.2 Setting

The coverage survey was undertaken in districts that implemented vaccination against JE in a routine immunization schedule by trained field teams. The JE-vaccinated districts of Maharashtra (six districts) and Telangana 16 districts) were considered (Figure 1). The survey was undertaken from October to December 2020. The Institutional Ethics Committees at ICMR-National Institute of Virology Pune, Government Medical College Nagpur, Mahatma Gandhi Institute of Medical Sciences at Sewagram, and Kakatiya Medical College Warangal (Telangana) approved the study protocol. We obtained written informed consent from parents or guardians before the interview.

3 RESULTS

3.2 JE vaccination coverage

The coverage of full immunization that is, receiving both doses of the live-attenuated SA 14-14-2 JE vaccine was above 90% in both states (Figure 2). The vaccinated children were cross-checked and verified through vaccination cards possessed by parents in 83.4% of cases and the rest through records kept at the public health facilities. In Maharashtra state, among 630 children surveyed, 597 (94.8%) were vaccinated. In Telangana state, among 445 children surveyed, 413 (92.8%) received both doses of the JE vaccine. The age-wise comparisons of coverage between Maharashtra and Telangana had a significant difference (p < 0.001). Age-wise percentage coverage significantly increased with an increase in age in Maharashtra state. However, it significantly decreased with an increase in age in Telangana state (Figure 3). The year-wise vaccination coverage was comparable in Maharashtra and Telangana states. However, in Maharashtra, the overall JE vaccination coverage was higher than in Telangana state from 2014 to 2017 (Figure 4). All comparisons of vaccination coverage between Maharashtra and Telangana states were statistically nonsignificant. There were no significant differences noted in urban-rural and boys−girls comparisons (Table 1).

Table 1. Japanese encephalitis vaccination coverage (%, with 95% CI) in Maharashtra and Telangana, 2020

Vaccination coverage	Maharashtra	Telangana
Overall	94.8 (92.7−96.3)	92.8 (90.0−94.9)
Area-specific
Urban	97.4 (93.5−98.9)	93.9 (88.4−96.8)
Rural	94.3 (91.8−98.0)	94.3 (91.1−96.3)
Gender-specific
Boys	94.1 (90.7−96.2)	94.3 (90.6−96.5)
Girls	95.3 (92.5−97.1)	94.0 (89.8−96.5)
Age-specific
<24 months	87.7 (79.4−93.0)	97.2 (92.0−99.0)
24−59 months	95.7 (93.3−97.2)	93.9 (90.3−96.1)
60 months or morea	96.6 (91.6−98.6)	80.3 (68.6−88.3)

• Note: The numbers presented above are percentages along with 95% CIs in brackets.
• Abbreviation: CI, confidence intervals.
• ^a The difference between states was significant.

4 DISCUSSION

The vaccination coverage studies are very important for assessing the local performance of vaccination programs.⁹ The JE endemic districts in Maharashtra and Telangana states report the incidence of JE and AES cases despite the implementation of the routine JE vaccination.^{6, 10} Therefore, we implemented a vaccination coverage survey to understand the level of uptake of JE vaccination and thus guide local health decisions on prioritization of prevention and control measures.

In summary, we found high JE vaccination coverage of above 90% in both states. In Maharashtra, the coverage and timeliness of both doses of JE vaccination in the routine schedule were slightly higher than in Telangana state. Most parents had retained the vaccination cards for their children indicating high awareness of parents. In Maharashtra state, coverage increased with an increase in the age of children. However, it was the opposite in Telangana state. The reasons for non-vaccination or delayed vaccination included the nonavailability of JE vaccine doses, the access of parents to the health centers, and their migration for work or employment. The timeliness of JE vaccination is acceptable. The additional risk factors like pigs, water birds, and paddy fields were higher in Telangana. The year-wise coverage had a similar pattern in Maharashtra and Telangana. We noticed good concordance between the JE and MR vaccine. This indicates favorable attitudes toward JE and other vaccinations. However, earlier studies in endemic areas in India have identified missed opportunities for vaccination uptake although vaccine effectiveness was acceptable.^{11, 12}

We selected the children who had an opportunity for receiving two doses of the JE vaccine. This allowed us for additional data collection for understanding coverage over the last 5 years period. Random selection of 7 children was done irrespective of the vaccination status of the child.² We could verify the vaccination details from the vaccination card provided by parents in most children and additional records maintained by healthcare workers. Studies reported earlier could hardly verify the vaccine doses using the vaccination cards, as they were not available to estimate vaccination coverage in India^{11, 12}; with only half of the guardians having vaccination cards with them outside India.¹³

A few JE cases were reported among adults from the study areas earlier indicating the shift of JE and AES cases from children to adult age groups.¹⁰ Some study groups have also noticed a similar shift from children to adult populations in other areas in India.^14-17 The JE vaccination in adults is not implemented in our study areas to date. However, a special campaign for JE vaccination in adults (>15 years) was implemented in Assam earlier.¹⁸ There is a need to monitor coverage among children along with the incidence of JE among endemic areas for assessing the need for changes in JE vaccination strategies in medium-endemic central India.

Studies have shown that the JE vaccine in routine immunization results in a decrease in JE cases.^19-24 The susceptible individuals will be prone to the risk of disease even though lower numbers of JE cases are observed after the implementation of JE vaccination programs. The neglected areas of medium-endemic central India have different seasonality.²⁵ Therefore, there is a need for further investigations, surveillance studies, follow-up, and management of JE cases as per the national guidelines for surveillance of AES recommended in sentinel sites supported with diagnostic testing.⁸ These studies would help in assessing the impacts of JE vaccination.

Confidence in vaccines and vaccination programs is very essential.²⁶ There are no such studies conducted on JE vaccination coverage and effectiveness in medium endemic areas in central India, although such studies are reported from epidemic and high-endemic regions in India.¹² If JE and AES cases continue to be reported despite high vaccination coverage, the effectiveness of vaccination may be considered for explaining the continued occurrence of JE and AES along with operational research aspects of vaccination programs.^{9, 11, 12}

In a study from the eastern part of India, 3 of the 4 children got at least one dose of the JE vaccine in the Gorakhpur division of Uttar Pradesh.¹¹ The coverage in 2015 had improved significantly over the period of 2 years.¹² The second dose coverage was low, with only 60% of children receiving the second dose of the JE vaccine. In a study in 2010 in Karnataka state, coverage was 92% in children as against the reported 83.85% in Mandya district; it was only 70.0% in Koppal, similar to the reported coverage of 69.8%.²⁷ JE vaccination coverage was high (93.0%) in Myanmar in 2018.²⁸ Our findings are similar to the study in the Yangon Region, Myanmar in 2019 which reported a high level (97.2%) of JE vaccination coverage.¹³ The high coverage is achievable with committed ground-level healthcare workers, despite the deficits in knowledge and perception about JE and AES indicating trust in the healthcare system.¹³ The program implementation monitoring may consider the coverage surveys.

As our study had very high JE vaccine coverage, the effectiveness of the existing and widely used live-attenuated SA 14-14-2 JE vaccine needs to be considered further. The effectiveness of the JE vaccine used in India is not available in JE medium-endemic regions although over 70% effectiveness is reported in high-endemic areas.²⁵ In India, low seroconversion rates have been documented post the live attenuated SA-14-14-2 vaccine, ranging from 58% to 74%, but the clinical significance remains unknown. Additionally, the dengue virus has been hypothesized to interfere with the immunogenicity of the SA-14-14-2 vaccine.²⁹ Emerging genotypes could also make the currently licensed vaccines, which are all genotype III JEV, ineffective; thus, there is a need to monitor predominantly circulating JEV genotypes.^{26, 29} There could also be a waning of neutralizing antibodies after the live attenuated vaccines, and this needs to be investigated further.³⁰ However, the recent paper presents evidence in support of evidence of cross-protection, although slightly lower than for the same genotype, offered against other genotypes in an experimental model using swine.³¹ This finding provides reassurance on the protection and effectiveness of existing genotype III JE vaccines, although this needs to be monitored for the effectiveness of current vaccines in humans in future.

We have a limitation of not reporting JE vaccination effectiveness study findings in this manuscript as it is being reported separately. Although the contribution of JE in AES cases has been reported to be around 10% in most JE high-endemic regions in the north and northeast India, the contribution of JE in medium-endemic regions in central India is slightly higher in our earlier reported studies among children⁶ and also in all age groups,¹⁰ as compared to the north and northeast India regions which experience seasonal outbreaks during postvaccination period. Also, there is a likelihood of some AES cases to be associated with JE, although not confirmed with available testing efforts, thereby having an expected decrease in AES cases. However, AES cases continued to be reported in central India regions signifying the possibility of non-JE causes.

There may be various issues including inadequate vaccine doses as indicated by parents. Thus, operational aspects including the availability of adequate doses and social reasons need to be considered. We had a limitation in implementing the JE vaccination coverage survey with a larger number of participants due to the COVID-19 pandemic restrictions in force. Also, we have planned to estimate coverage levels at the state and regional levels only. Therefore, we could not estimate coverage levels at the district level and undertake the comparisons.

5 CONCLUSIONS

In conclusion, JE vaccination coverage was high in Maharashtra and Telangana states in India. However, the focus needs to be on reducing missed opportunities for routine vaccination. The vaccination effectiveness studies among children could help in explaining the continued occurrence of JE. The impact of JE vaccination on reducing the incidence of disease may be helpful for deciding control strategies.

AUTHOR CONTRIBUTIONS

Babasaheb V. Tandale planned and designed the study including the design, procedures, and questionnaires. Critical review inputs were received from Pradeep R. Deshmukh, Uday W. Narlawar, and Punam Kumari Jha. Additional review, suggestions, and coordination of field activities were received from Rahul Narang, Mohiuddin S. Qazi, and Goteti V. Padmaja as the site investigators. The other investigator colleagues of the study group also provided inputs and support during the study execution (Shilpa J. Tomar, Vijay P. Bondre, Gajanan N. Sapkal, Rekha G. Damle, Poornima Khude, Manoj Talapalliwar, Pragati Rathod, and Kishore Kumar K. J.). Pravin S. Deshmukh drafted the manuscript along with the preparation of illustrations with guidance from Babasaheb V. Tandale and others. Shekhar S. Rajderkar guided, reviewed, and provided inputs on study design, data interpretation, and reporting of findings along with a critical review of the draft report and final manuscript. All authors and study group contributors reviewed and approved the final manuscript.

CONFLICT OF INTEREST

The authors declare no conflict of interest.