key: cord-1049282-wiz6pu51 authors: Sekhar Bose, Anindya; Rai, Pasang; Prasad Gupta, Binod; Pradhan, Rahul; Lacoul, Mona; Shakya, Sushil; Shrestha, Dipesh; Gautam, Abhiyan; Bhandari, Bharat; Shrestha, Basanta; Singh Tinkari, Bhim; Jha, Runa; Khanal, Basudha; Shrestha, Pradeep; Bhusal, Sushma; Sharma Gautam, Jhalak title: Nepal Measles outbreak response immunization during COVID-19: a risk-based intervention strategy date: 2022-02-28 journal: Vaccine DOI: 10.1016/j.vaccine.2022.02.057 sha: 17730e77a73effda5bc3f3df41e61e66b6fe5d79 doc_id: 1049282 cord_uid: wiz6pu51 In 2020, National Immunization Programme (NIP) of Nepal implemented a measles outbreak response immunization (ORI) campaign, which was additional to an ongoing preventive measles-rubella SIA campaign. Both campaigns were implemented during ongoing COVID-19 transmission. By April, 220 measles cases and two deaths were confirmed from eight districts of Nepal. The NIP triangulated information from surveillance (measles and COVID-19), measles immunization performance and immunity profile, programme capacities and community engagement and applied a logical decision-making framework to the collated data to inform ‘Go/No-Go’ decisions for ORI interventions. This was reviewed by the National Immunization Advisory Committee (NIAC) for endorsement. Outbreak response with non-selective immunization (ORI), vitamin-A administration and case management were implemented in affected municipalities of four districts, while in the remaining districts outbreak response without ORI were undertaken. The structure and iterative application of this logical framework has been described. ORI was implemented without interrupting the ongoing measles-rubella vaccination campaign which had targeted children from 9 to 59 months of age. The age group for ORI was same as SIA in one sub-district area, while for the other three sub-district areas it was from 6 months to 15 years of age. More than 32,000 persons (97% coverage) were vaccinated in ORI response. Overall measles incidence decreased by 98% after ORI. The daily incidence rate of measles was 94 times higher (95% confidence interval: 36.11 – 347.62) before the ORI compared to two weeks after ORI until year end. Close attention to surveillance and other data to inform actions and seamless collaboration between NIP and core immunization partners (WHO, UNICEF), with guidance from NIAC were key elements in successful implementation. This was an example of feasible application of the global framework for implementation of a mass vaccination campaign during COVID-19 through application of a simple decision-making logical framework. Measles is a highly infectious and lethal disease caused by paramyxovirus and usually transmitted through aerosolized respiratory droplets. In 2019, the World Health Organization (WHO) estimated that there were 9.8 million cases and 0.2 million deaths from measles globally [1] . The reported number of cases was highest since 1996, largely driven by major outbreaks in several countries. Strengthening capacities for outbreak response is a strategic priority of the Measles and rubella strategic framework 2021-2030 [2]. In Nepal, substantial progress has been made towards measles elimination. Confirmed measles case occurrence has reduced by 98% between 2003 and 2017 [3] . Confirmed rubella cases had decreased by 97% between 2008 and 2017 which was certified by the WHO Regional Verification Commission [4] However, from 2018 to 2019 confirmed measles cases had increased by 66% (260 to 431). The National Immunization Programme (NIP) of Nepal had planned to conduct a nationwide campaign with measles rubella (MR) vaccine in late 2019, but owing to some operational considerations, MR campaign was shifted to first half of 2020. The MR campaign had planned to vaccinate 9-59-month-old children in two one-month phases, in February-March and March-April 2020. NIP completed the first phase as scheduled. However, the second phase was extended because of the COVID-19 situation in Nepal. The first and second COVID-19 cases in Nepal were reported on 23 January and 23 March 2020 respectively. From 23 March till 7 September 2020, 46,257 confirmed cases of COVID-19 with 289 deaths were reported in Nepal [5] . Government of Nepal (GoN) declared a national lockdown starting 24 March 2020 [6] . The sudden declaration of lockdown also impacted on delivery of all routine health services and the MR campaign. The second phase of MR campaign was thus delayed by more than a month and was finally completed by 7 July 2020. In the first quarter of 2020, the vaccine preventable disease (VPD) surveillance programme in Nepal observed an increasing incidence of measles cases in age groups above five years. At this time, the MR-SIA was interrupted due to nationwide lock-down, while measles outbreaks were occurring in and spreading across several districts. The National Immunization Programme (NIP) continually reviewed surveillance data for measles as well as COVID-19 cases, assessed magnitude of measles outbreak cases, deaths and other epidemiological parameters as described below, and took informed decisions on outbreak-by-outbreak basis to implement outbreak response immunization (ORI) after assessing risk of measles morbidity and mortality vis-a-vis risk of COVID-19 occurrence in the outbreak affected areas. This report documents the epidemiologic rationale, application of existing policy guidelines, programmatic decision-making processes, and how a simple logical framework was adapted to inform decisions for risk-based ORI. We also describe how the National Immunization Advisory Group (NIAC) which functions as the National Immunization Technical Advisory Group (NITAG) for Nepal provided technical advice and recommendations to guide the NIP. The case-based measles surveillance system in Nepal investigates and confirms (through serology) every suspected measles case in the country. WHO-Nepal's Immunization Preventable Disease (WHO-IPD) programme provides technical assistance to the Family Welfare Division (FWD) and to public health laboratories for VPD surveillance. A dedicated team of WHO surveillance medical officers, coordinates with a nationwide reporting network of nearly 1500 health facilities and clinics in public and private sectors for VPD surveillance case reporting and investigation. WHO-Nepal also provided technical assistance during COVID-19 pandemic for surveillance and response. Case and outbreak definitions: A suspected measles case was a person of any age with fever and maculopapular (non-vesicular) rash or a person in whom a health care worker suspects measles [7] . Occurrence of five or more suspected measles cases from a municipal ward or contiguous wards of the same or adjoining municipalities (rural or urban) as a rolling total over a period of any four consecutive weeks was the operational definition for a suspected measles outbreak [8]. The VPD surveillance programme tests blood samples from every sporadic suspected case and from five to ten cases from each suspected outbreak. WHO accredited (National Public Health laboratory, (NPHL) Kathmandu) and proficient (BP Koirala Institute of Health Sciences (BPKIHS), Dharan) laboratories conduct laboratory tests for Immunoglobulin-M (IgM) antibodies for confirmation of measles, and for rubella if negative for measles [9] . A suspected case was confirmed (measles or rubella) based on IgM serology result. Please see supplementary information for further details on laboratory procedures followed. A suspected outbreak was confirmed when at least two suspected cases from an outbreak tested IgM positive for either measles or rubella. Cases from a suspected outbreak from whom no samples were collected were confirmed through epidemiological linkage with other laboratory confirmed or epidemiologically confirmed cases. Sporadic cases from whom no samples were collected, were confirmed as clinically compatible based on presenting symptoms and signs (along with fever and rash, and either cough, coryza or conjunctivitis at onset for a case to be measles compatible). As per case classification algorithm, a confirmed case in this report is defined as a suspected case that was either laboratory confirmed, or epidemiologically confirmed (i.e. epidemiologically linked) or was clinically compatible. A measles death was defined as a death occurring within 30 days of onset of rash in a confirmed measles case, which was not due to another unrelated cause like trauma etc. Outbreak closure and outbreak duration: As per national surveillance guidelines a suspected measles outbreak was declared closed when at least 21 days had passed without occurrence of any suspected measles cases after onset of rash of the last case [10]. However, in practice public health workers, would follow up until 30 days from onset of last case to ascertain any measles related deaths as well as to validate absence of fresh cases for closure of the outbreak. The duration of an outbreak was the difference between the dates of onset of the first and last detected cases. In 2020, a nationwide SIA campaign was planned for all 77 districts with MR vaccine with add-on bivalent oral polio vaccine (bOPV) in 19 districts in two phases. Phase -1 was conducted from 13 February to 13 March in provinces 1, 2 and 5 (now renamed Lumbini province). Phase-2 was started on 14 March in the remaining provinces (Bagmati, Gandaki, Karnali and Sudurpaschim) with a plan for completing the activity within a month. It was interrupted from 24 March due to national lockdown because of COVID-19, resumed in May and finally completed by 7 July 2020. The target age-group for the MR-SIA campaign was 9-59-month-old children and for bOPV it was 0-59-month-old children irrespective of their past MR or OPV vaccination status. Measles outbreak response mechanisms and decision framework: WHO-Nepal IPD programme collects and continuously reviews measles surveillance information (case and lab results) and shares updates with the NIP and Family Welfare Division (FWD) and immunization partners (WHO and UNICEF) and the National immunization Advisory Committee (NIAC). The Department of Health Services has formulated programme guidelines for responding to measles outbreaks including through ORI [11] . The guidelines have provisions for non-selective ORI for target age groups from six or nine months of age to five, ten or fifteen years of age. However, these guidelines were drawn up in 2019 before the COVID-19 pandemic and thus did not include an explicit logical framework for examining competing risks from another disease or hazard to inform decisions to conduct ORI. To inform the decision to undertake (or withhold or defer) an outbreak response immunization (ORI) the NIP used the following dimensions -programme mandate for ORI, direct risk of measles transmission, competing or indirect risk of COVID-19 transmission, community demand and ownership of ORI, operational feasibility including availability of vaccine supplies and other logistics and local programme capacity for implementing ORI. Under each dimension, the NIP collected quantitative and qualitative information and intelligence as detailed below to help inform the final decision for action. 1. Programme mandate for ORI: Existing mandate and any set procedures for the national immunization programme to undertake ORI. 2. Direct epidemiological risk of measles transmission: Number of measles cases and deaths, risk or evidence of contiguous spread between wards, municipalities, and districts, age group affected (within and beyond SIA target age group) and immunity gap. Disproportionate burden of disease in one or more specific underserved communities. 6. Local programme capacity for ORI: Capacity of the local programme functionaries to implement measles ORI safely and effectively was assessed. This assessment also included operational feasibility like availability of trained human resources, vaccine, ancillary equipment including personal protective equipment and waste management. The sequential list above is for descriptive purposes only. The process was undertaken by updating available data and analyses through multiple iterations. On 30 April 2020, NIP along with partners, WHO and UNICEF presented all collated information to the NIAC including a competing risk analysis for each outbreak or cluster of outbreaks and sought its concurrence on actions undertaken and recommendations and guidance for future response. Statistical methods: Surveillance data were extracted from the web-based surveillance database module developed by WHO-IPD and used by NIP. Immunization coverage data was extracted from reports available with NIP. Descriptive statistical measures (per cent age distribution and vaccination status, spatial distribution maps for cases, per cent coverage etc.) were used to describe the epidemiology of the outbreaks. Daily incidence rate (DIR) of confirmed measles cases per million persons was computed for a district as below: Confirmed measles cases were partitioned into three mutually exclusive time periods as per dates of rash onset. Period A was from 1 January 2020 to end date of ORI for the district. The buffer period was from end date of ORI to 14 days after ORI for that district. Period B was from end date of buffer period for a district to 31 December 2020. The DIR of measles were compared between two time-periods A and B by computing DIR ratios for each district and overall, by dividing DIR in period A by DIR in period B. Cases occurring during the buffer period were excluded as we assumed it would take at least 14 days from the time of vaccination to develop immunity. Similar exclusion of cases during buffer periods of two or three weeks have been reported by other authors [12, 13] . DIR ratios between the two time periods were tested for statistical significance at 95% level. The statistical software package, Stata version 15.0 was used for statistical tests for computing incidence rate ratio and 95% confidence interval for hypotheses testing for impact of ORI on risk of measles. . Measles surveillance is part of the national surveillance programme for diseases of public health importance. Being part of a national programme, explicit individual consent is not sought for investigation and blood sample collection, but individual and/or community participation is coordinated by local public health authorities. Participation in the surveillance programme is entirely voluntary. All data collected are stored securely and individual identifiers are not shared publicly. Laboratory results are usually communicated back to individuals (for sporadic cases) and to the community (for outbreaks) through local public health teams. Between 1 January and 29 April 2020, VPD surveillance programme notified 11 laboratory confirmed measles outbreaks in eight districts of Nepal including the largest number of cases from a cluster of four outbreaks in Dhading district (Table 1) . Two measles deaths occurred in the Dhading cluster. No measles deaths were reported from any of the other outbreaks. Initial analysis showed that as many as 78% (172/220) of the confirmed measles cases were beyond the age group targeted through the MR SIA campaign. Of these, 60% (104/172) were in the 5-14- year-old age group, in which only about 10% of cases gave a history of vaccination with measles containing vaccine. Timeline and spread of Dhading outbreak cluster: The Dhading district outbreak cluster (138 cases) had the earliest onset of cases in February and continued for the longest period of 72 days. The first two clusters of cases were detected on 4 February 2020 and 29 February 2020 from two wards of Benighat-Rorang rural municipality in the district, spreading quickly to other wards of the rural municipality. In addition, there were few cases in neighbouring municipalities (Palika) too. Analyses of case-based surveillance data revealed that some underserved communities were being disproportionately affected with 95% (131/138) of cases from underserved ethnic groups. In April, the outbreak spread beyond Dhading to contiguous municipalities in Gorkha and Chitwan districts and all the outbreak related cases were from the same underserved groups in these districts (Table-1 There were also demands from other outbreak affected districts like Kathmandu and Jhapa for an ORI. NIP decided to seek advice from NIAC on a logical framework for Go/No-go decisions for measles ORI in COVID-19 context. All available information was placed before the National Immunization Advisory Committee in its meeting on 30 April 2020. To facilitate structured progression to an informed decision, the logical framework considered the Immunization session sites also provided handouts on COVID-19 prevention measures. In addition, supportive supervision and monitoring was conducted by FWD, provinces and districts and partners. The target age group was 9 months to 5 years of age in Gandaki rural municipality, Gorkha district, Gandaki province. In the remaining areas (municipalities in Dhading, Chitwan and Kathmandu districts -Bagmati province) the target age group for ORI was 6 months to 15 years of age. The total target was 32,150 and 97% of the target age group was immunized ( Table 3 ). The national measles ORI guideline was adapted for this ORI response during active COVID-19 transmission. These included a Impact of ORI: ORI was effective in reducing measles cases by 98% (Table 4 ). The ratio of daily incidence rates of measles cases per million population between two time periods pre-ORI (period A) and post-buffer (period B) showed that the daily incidence was significantly reduced overall in each district separately at 95% level of confidence. For all four districts combined, the incidence risk ratio was 94 times higher in pre-ORI period compared to the post buffer period (95% CI: 36.11 -347.62). The ORI decision in Nepal was optimally timed for stopping expansion of outbreaks. The first confirmed outbreak from one ward of Benighat-8 Rorang Rural Municipality of Dhading district spread across several wards of same municipality and later to two adjacent districts -Gorkha and 9 Chitwan making a contiguous block of three districts. This outbreak cluster continued from 4 February to end of April 2020 resulting in total of 10 166 measles cases including two deaths. ORI was conducted in affected municipalities in these three districts between 29 April to 13 May 2020 11 (Tables 2 and 3) . However, no ORI response was conducted for outbreaks in several other districts (Jhapa, Morang, Sarlahi and Lalitpur). While more than 80% of 13 cases in these outbreaks were beyond SIA target age group, no underserved community was affected and there was no community demand for 14 ORI response and there were no measles deaths. E37323788S5_Out.docx 17 15 The success of this program experience and the processes followed clearly demonstrated that this approach was feasible and practicable within 16 existing resources at country level when decisions needed to be taken and choices made in a complex environment faced with two lethal 17 infectious diseases simultaneously. Of note, these decisions were based on triangulating surveillance data (for both measles and COVID-19) and 18 programmatic data from different sources like real time epidemiological data, immunization programme information and community related 19 information and these were taken collectively and iteratively with close collaboration between the NIP, core immunization partners (WHO and 20 UNICEF) and the NIAC, which is the mandated national immunization technical advisory group in Nepal. COVID-19 surveillance data was also 21 accessed. The WHO-IPD immunization team was also supporting COVID-19 surveillance. By the end of May 2020, the World Health Organization published a framework document for decision-making regarding implementation of 23 mass vaccination campaigns in the context of COVID-19 [15] . The logical decision-making approach described here pre-dated publication of this 24 WHO document. However, there is a close alignment between Nepal NIP experience and practice and the global framework demonstrating that 25 the WHO framework document is indeed adaptable and implementable in a country context. In fact, the Nepal experience can well serve as an 26 example of application of the principles laid out in the WHO framework document, as adapted to small-scale ORI responses which were right 27 sized to respond to four sub-district areas ( Table 3 ). The technical support and resources deployed were all available within the country and 28 were fully owned up by the MOHP and the programme divisions. The Nepal NIP applied multiple iterative decision-making loops to reach a proposed solution that was finally endorsed by NIAC rather than a 30 rigidly sequential algorithmic approach. Community engagement, acceptance and demand for ORI including from local opinion leaders was Table 4 : Impact of ORI: confirmed measles cases before ORI, during buffer period and after buffer period until end of year; daily incidence rate (DIR) per million persons and incidence risk ratio by district before ORI and after buffer period The opinions expressed by the authors are their own, and do not necessarily reflect that of their organizations. Any proprietary names mentioned in this manuscript do not indicate endorsement of the product(s) by any of the authors or their respective organizations. WHO-IPD is supported by donor funding majorly from Gavi the vaccine alliance, the Global Polio Eradication Initiative (GPEI), the Centers for Disease Control (CDC), Atlanta and others, but no separate funding was received for this work. The donors had no role in data collection, analysis or in final decision to submit this work for publication. The authors declare that they have no known competing financial interests or personal relationships that could have influenced or appeared to influence the work reported in this paper. World Health Organization, Measles and rubella strategic framework 2021-2030, World Health Organization Joint National and International Measles, Rubella and Congenital Rubella Syndrome Programme Review Third Meeting of the South-East Asia Regional Verification Commission for Measles Elimination and Rubella/Congenital 127 Report of the Third Meeting of the SEA Regional Verification Commission World Health Organization Nepal, COVID-19 Nepal Situation Ministry of Health and Population, Responding to COVID-19: Health sector preparedness, response and lessons learnt Department of Immunization and Vaccine Development, Guidelines on Verification of Measles Elimination and Rubella/Congenital 135 World Health Organization Regional Office for South-East Asia World Health Organization, Response to measles outbreaks in measles mortality reduction settings, World Health Organization Department of Immunization and Vaccine Development, SEAR MR lab network Ministry of Health and Population, Government of Nepal, Field guide for surveillance of vaccine preventable diseases, Government 142 of Nepal Family Welfare Division, Measles Outbreak Response Immunization (ORI) Guidelines, Department of Health Services, Ministry of Health and 144 Population, Government of Nepal Measles is a steady, silent killer among COVID-19 | MSF World Health Organization, Framework for decision-making: implementation of mass vaccination campaigns in the context of COVID-19: 150 interim guidance Department of Immunization Vaccine and Biologicals, IMMUNIZATION AGENDA 2030: A global strategy to leave no one behind, World 152 Health Organization Western Pacific surveillance and response journal : WPSAR Family Welfare Division, WHO-IPD Nepal, Monthly VPD surveillance and Immunization update Nepal 102 The authors declare that they have no known competing financial interests or personal relationships that could have influenced or appeared to 104 influence the work reported in this paper.