Responding to COVID-19 vaccine-related safety events: WHO Western Pacific regional experience and lessons learned.

Problem: Novel vaccines were developed in an unprecedentedly short time in response to the global coronavirus disease (COVID-19) pandemic, which triggered concerns about the safety profiles of the new vaccines. This paper describes the actions and outcomes of three major adverse events of special interest (AESIs) reported in the World Health Organization's (WHO's) Western Pacific Region: anaphylaxis, thrombosis with thrombocytopenia syndrome (TTS) and post-vaccination death. Context: During the large-scale introduction of various novel COVID-19 vaccines, robust monitoring of and response to COVID-19 vaccine safety events were critical. Action: We developed and disseminated information sheets about anaphylaxis and TTS; provided tailor-made training for anaphylaxis monitoring and response, webinars about TTS and AESIs, and an algorithm to support decision-making about AESIs following immunization; as well as provided country-specific technical support for causality assessments, including for possible vaccination-related deaths. Outcome: Each major vaccine event and situation of high concern was responded to appropriately and in a timely manner with comprehensive technical support from WHO. Our support activities have not only strengthened countries' capacities for vaccine safety surveillance and response, but also enabled countries to decrease the negative impact of these events on their immunization programmes and maintain the confidence of health-care professionals and the general population through proactive delivery of risk communications. Discussion: This paper summarizes selected, major AESIs following COVID-19 vaccination and responses made by WHO's Regional Office for the Western Pacific to support countries. The examples of responses to vaccine safety events during the pandemic and unprecedented mass vaccination campaigns could be useful for countries to adopt, where applicable, to enhance their preparation for activities related to monitoring vaccine safety.

COVID-19 vaccine-related adverse events following immunization in the WHO Western Pacific Region, 2021-2022.

The speed at which new vaccines against coronavirus disease (COVID-19) were developed and rolled out as part of the global response to the pandemic was unprecedented. This report summarizes COVID-19 vaccine-related safety data in the World Health Organization Western Pacific Region. Data for 1 March 2021 to 31 March 2022 from 36 out of 37 countries and areas in the Western Pacific Region are presented. More than 732 million doses of eight COVID-19 vaccines were administered; reporting rates of adverse events following immunization (AEFIs) and serious AEFIs were 130.1 and 5.6 per 100 000 doses administered, respectively. Anaphylaxis, thrombosis with thrombocytopenia syndrome, and myocarditis/pericarditis were the most frequent COVID-19 adverse events of special interest (AESIs) reported. The reported rates of AESIs in the Western Pacific Region were within the range of expected or background rates. Vaccine benefits far outweigh the risk of reported serious adverse reactions and serious outcomes of COVID-19. Continued AEFI surveillance is recommended to better understand and ensure the safety profiles of novel COVID-19 vaccines.

Anaphylaxis: Revision of the Brighton collaboration case definition.

The Brighton Collaboration (BC) has formulated a number of case definitions which have primarily been applied to adverse events of special interest in the context of vaccine safety surveillance. This is a revision of the 2007 BC case definition for anaphylaxis. Recently, the BC definition has been widely used for evaluating reports of suspected anaphylaxis following COVID-19 vaccination. This has led to debate about the performance of the BC definition in comparison with those from the US National Institute of Allergy and Infectious Disease/Food Allergy Anaphylaxis Network (NIAID/FAAN) and the World Allergy Organization (WAO). BC convened an expert working group to revise the case definition based on their usual process of literature review and expert consensus. This manuscript presents the outcome of this process and proposes a revised case definition for anaphylaxis. Major and minor criteria have been re-evaluated with an emphasis on the reporting of observable clinical signs, rather than subjective symptoms, and a clearer approach to the ascertainment of levels of certainty is provided. The BC case definition has also been aligned with other contemporary and international case definitions for anaphylaxis.

Use of a catch-up programme to improve routine immunization in 13 provinces of Papua New Guinea, 2020-2022.

Objective: Routine immunization coverage in Papua New Guinea has decreased in the past 5 years. This persistently low routine immunization coverage has resulted in low population immunity and frequent outbreaks of vaccine-preventable disease across the country. We describe the use of a catch-up programme to improve routine immunization during the coronavirus disease pandemic in Papua New Guinea during 2020-2022. Methods: In June 2020, 13 provinces of Papua New Guinea were selected to undergo a vaccination catch-up programme, with technical support from the World Health Organization (WHO) and the United Nations Children's Fund. Twelve provinces received financial and logistic support through the Accelerated Immunization and Health Systems Strengthening programme, and one received support from WHO. All stakeholders were involved in planning and implementing the catch-up programme. Results: Between July 2020 and June 2022, about 340 health facilities conducted catch-up activities. The highest number of children aged under 1 year were vaccinated in 2022 (n = 33 652 for third dose of pentavalent vaccine). The national coverage of routine immunization (including the catch-up vaccinations) increased between 2019 and 2020 - by 5% for the third dose of pentavalent vaccine, 11% for the measles-rubella vaccine and 16% for the inactivated poliovirus vaccine. The coverage declined slightly in 2021 before increasing again in 2022. Discussion: The catch-up programme was an instrumental tool to improve routine immunization coverage between 2020 and 2022 and during the pandemic in Papua New Guinea. With appropriate technical and logistic support, including financial and human resources, catch-up programmes can strengthen routine immunization coverage across the country.

Assessing perceptions of establishing a vaccine pooled procurement mechanism for the Western Pacific Region.

This study explored the demand and interest among countries in the World Health Organization Western Pacific Region (WPR) to establish and participate in a regional vaccine pooled procurement mechanism. National counterparts affiliated with Ministries of Health that are involved in the national procurement of vaccines within the WPR were identified and invited to complete surveys. Out of 80 counterparts invited, 17 (21%) responded, representing 13 of the 27 WPR countries. Five countries expressed interest in participating in a regional pooled procurement mechanism, 3 expressed lack of interest and 5 did not respond to the question. Preferred characteristics of the procurement mechanism, included flexible participation (i.e. non-compulsory), payment in local currency before receipt of goods and a fixed price for vaccines (i.e. not tiered pricing). Vaccine pricing disparities were noted among upper middle-income and high-income countries for five of the 13 routine vaccines surveyed. Eight countries listed budget planning, quality of vaccines, timely delivery, cost-saving and payment after receipt as potential benefits of pooled procurement.

An approach for preparing and responding to adverse events following immunization reported after hepatitis B vaccine birth dose administration.

The success of immunization programs in lowering the incidence of vaccine preventable diseases (VPDs) has led to increased public attention on potential health risks associated with vaccines. As a result, a scientifically rigorous response to investigating reported adverse events following immunization (AEFI) and effective risk communications strategies are critical to ensure public confidence in immunization. Globally, an estimated 257 million people have chronic hepatitis B virus (HBV) infection, which causes more than 686,000 premature deaths from liver cancer and cirrhosis. Hepatitis B vaccination is the most effective way to prevent mother-to-child transmission of HBV infection, especially when a timely birth dose is given within 24 h of birth. However, an infant's risk of dying is highest in the neonatal period, and thus, administering HepB-BD within 24 h of birth overlaps with the most fragile period in an infant's life. A working group formed in July 2016 following the publication of the case reports of the effects on vaccination coverage of media reports of infant deaths after HepB-BD administration in China and Vietnam. The goal of the working group was to create a framework and describe best practices for preparing for and responding to AEFI reported after HepB-BD administration, using existing resources. The framework includes six steps, including three preparation steps and three response steps. This document is written for national and regional immunization program staff. Prior to using the framework for preparation and response to AEFIs reported after HepB-BD administration, staff members should be familiar with how AEFI are detected, reported, and investigated in the country. The document might also be of interest to national regulatory staff members who monitor vaccine safety within the country.

Engagement of private providers in immunization in the Western Pacific region.

Financial sustainability of national immunization programmes (NIPs) in the Western Pacific is a growing concern. In the face of decreasing donor support for public immunization programmes, the role of private providers is becoming growingly important in attaining and sustaining programme achievements. Two-thirds of Member States in the Region have engaged the private sector in their immunization programmes, however little is known about the range and type of engagement. A survey was conducted in 2016 to map the scope and characteristics of private provider involvement, in order to inform guidance for decision makers. 14 countries participated, with responses from NIPs, national regulatory agencies, national immunization technical advisory groups (NITAGs), and private providers (defined as any entity other than the government). Findings revealed that most countries have policies and regulations concerning private providers, but 50% of private provider respondents were unaware that such policies are available. In most countries private providers' contribution is limited to less than 10% of the total target population. Private providers in only 6 countries surveyed follow the vaccination schedule recommended by the NIP, with demand by vaccine recipients being the main cause of deviation. A majority (>70%) of private provider respondents believe that clients seeks their services not because of perception of quality, but to access new vaccines unavailable through the NIP. Private providers in all countries received vaccines from the NIP at no cost, for which they only charge clients a service fee. The majority of private providers received training from the NIP, whereas only around 25% of them received training from their own institutions. Private providers from 11 countries share EPI performance data and adverse events following immunization, however, NIPs perceive this data as suboptimal. Private providers have a limited role in decision making processes, such as NITAGs. Further effective engagement of private sector providers has the potential to improve overall efficiency of immunization service delivery.

Analysis of Dengue Serotype 4 in Sri Lanka during the 2012-2013 Dengue Epidemic.

The four serotypes of dengue virus (DENV-1, -2, -3, and -4) have had a rapidly expanding geographic range and are now endemic in over 100 tropical and subtropical countries. Sri Lanka has experienced periodic dengue outbreaks since the 1960s, but since 1989 epidemics have become progressively larger and associated with more severe disease. The dominant virus in the 2012 epidemic was DENV-1, but DENV-4 infections were also commonly observed. DENV-4 transmission was first documented in Sri Lanka when it was isolated from a traveler in 1978, but has been comparatively uncommon since dengue surveillance began in the early 1980s. To better understand the molecular epidemiology of DENV-4 infections in Sri Lanka, we conducted whole-genome sequencing on dengue patient samples from two different geographic locations. Phylogenetic analysis indicates that all sequenced DENV-4 strains belong to genotype 1 and are most closely related to DENV-4 viruses previously found in Sri Lanka and those recently found to be circulating in India and Pakistan.

A Spatial Hierarchical Analysis of the Temporal Influences of the El Niño-Southern Oscillation and Weather on Dengue in Kalutara District, Sri Lanka.

Dengue is the major public health burden in Sri Lanka. Kalutara is one of the highly affected districts. Understanding the drivers of dengue is vital in controlling and preventing the disease spread. This study focuses on quantifying the influence of weather variability on dengue incidence over 10 Medical Officer of Health (MOH) divisions of Kalutara district. Weekly weather variables and data on dengue notifications, measured at 10 MOH divisions in Kalutara from 2009 to 2013, were retrieved and analysed. Distributed lag non-linear model and hierarchical-analysis was used to estimate division specific and overall relationships between weather and dengue. We incorporated lag times up to 12 weeks and evaluated models based on the Akaike Information Criterion. Consistent exposure-response patterns between different geographical locations were observed for rainfall, showing increasing relative risk of dengue with increasing rainfall from 50 mm per week. The strongest association with dengue risk centred around 6 to 10 weeks following rainfalls of more than 300 mm per week. With increasing temperature, the overall relative risk of dengue increased steadily starting from a lag of 4 weeks. We found similarly a strong link between the Oceanic Niño Index to weather patterns in the district in Sri Lanka and to dengue at a longer latency time confirming these relationships. Part of the influences of rainfall and temperature can be seen as mediator in the causal pathway of the Ocean Niño Index, which may allow a longer lead time for early warning signals. Our findings describe a strong association between weather, El Niño-Southern Oscillation and dengue in Sri Lanka.

Laboratory-Enhanced Dengue Sentinel Surveillance in Colombo District, Sri Lanka: 2012-2014.

INTRODUCTION: Dengue has emerged as a significant public health problem in Sri Lanka. Historically surveillance was passive, with mandatory dengue notifications based on clinical diagnosis with only limited laboratory confirmation. To obtain more accurate data on the disease burden of dengue, we set up a laboratory-based enhanced sentinel surveillance system in Colombo District. Here we describe the study design and report our findings of enhanced surveillance in the years 2012-2014. METHODS: Three outpatient clinics and three government hospitals in Colombo District that covered most of the Colombo metropolitan area were selected for the sentinel surveillance system. Up to 60 patients per week presenting with an undifferentiated fever were enrolled. Acute blood samples from each patient were tested by dengue specific PCR, NS1 ELISA and IgM ELISA. A sub-set of samples was sent to Duke-NUS Singapore for quality assurance, virus isolation and serotyping. Trained medical research assistants used a standardized case report form to record clinical and epidemiological data. Clinical diagnoses by the clinicians-in-charge were recorded for hospitalized cases. RESULTS: Of 3,127 febrile cases, 43.6% were PCR and/or NS1 positive for dengue. A high proportion of lab confirmed dengue was observed from inpatients (IPD) (53.9%) compared to outpatient (clinics in hospitals and general practice) (7.6%). Dengue hemorrhagic fever (DHF) was diagnosed in 11% of patients at the time of first contact, and the median day of illness at time of presentation to the sentinel sites was 4. Dengue serotype 1 was responsible for 85% of the cases and serotype 4 for 15%. The sensitivity and specificity of the clinicians' presumptive diagnosis of dengue was 84% and 34%, respectively. CONCLUSION: DENV-1, and to a lesser degree DENV-4, infection were responsible for a high proportion of febrile illnesses in Colombo in the years 2012 to 2014. Clinicians' diagnoses were associated with high sensitivity, but laboratory confirmation is required to enhance specificity.

Costs of Dengue Control Activities and Hospitalizations in the Public Health Sector during an Epidemic Year in Urban Sri Lanka.

BACKGROUND: Reported as a public health problem since the 1960s in Sri Lanka, dengue has become a high priority disease for public health authorities. The Ministry of Health is responsible for controlling dengue and other disease outbreaks and associated health care. The involvement of large numbers of public health staff in dengue control activities year-round and the provision of free medical care to dengue patients at secondary care hospitals place a formidable financial burden on the public health sector. METHODS: We estimated the public sector costs of dengue control activities and the direct costs of hospitalizations in Colombo, the most heavily urbanized district in Sri Lanka, during the epidemic year of 2012 from the Ministry of Health's perspective. The financial costs borne by public health agencies and hospitals are collected using cost extraction tools designed specifically for the study and analysed retrospectively using a combination of activity-based and gross costing approaches. RESULTS: The total cost of dengue control and reported hospitalizations was estimated at US$3.45 million (US$1.50 per capita) in Colombo district in 2012. Personnel costs accounted for the largest shares of the total costs of dengue control activities (79%) and hospitalizations (46%). The results indicated a per capita cost of US$0.42 for dengue control activities. The average costs per hospitalization ranged between US$216-609 for pediatric cases and between US$196-866 for adult cases according to disease severity and treatment setting. CONCLUSIONS: This analysis is a first attempt to assess the economic burden of dengue response in the public health sector in Sri Lanka. Country-specific evidence is needed for setting public health priorities and deciding about the deployment of existing or new technologies. Our results suggest that dengue poses a major economic burden on the public health sector in Sri Lanka.

An approach to death as an adverse event following immunization.

Co-incidental death occurring proximate to vaccination may be reported as an adverse event following immunization. Such events are particularly concerning because they may raise community and health provider concerns about the safety of the specific vaccine and often the immunization programme in general. Coincidental events need to be differentiated from vaccine reactions, such as anaphylaxis, which may very rarely result in death. In 2013, the World Health Organization (WHO) released an updated manual for the Causality Assessment of an AEFI. The purpose of this review is to apply the WHO causality methodology to death when this is reported as an AEFI. The causality assessment scheme recommends a four step process to enable classification of the AEFI and to differentiate events which are causally consistent from those that are inconsistent with immunization. However, for some events causality maybe indeterminate. Consistent causal reactions that may result in death are very rare and maybe related to the vaccine product (e.g. anaphylaxis, viscerotrophic disease), vaccine quality defect (e.g. an incompletely attenuated live vaccine agent) or an immunization error (e.g. vaccine vial contamination). Events that are inconsistent with immunizations are due to co-incidental conditions that may account for infant and childhood mortality. In countries with a high infant mortality rate the coincidental occurrence of death and immunization may occur not infrequently and a robust mechanism to obtain information from autopsy and perform an AEFI investigation and causality assessment is essential. Communication with the community and all stakeholders to maintain confidence in the immunization programme is critical.

Sustainable dengue prevention and control through a comprehensive integrated approach: the Sri Lankan perspective.

Dengue is a leading public health problem in Sri Lanka. All 26 districts and all age groups are affected, with high disease transmission; the estimated average annual incidence is 175/100 000 population. Harnessing the World Health Organization Global strategy for dengue prevention and control, 2012-2020, Sri Lanka has pledged in its National Strategic Framework to achieve a mortality from dengue below 0.1% and to reduce morbidity by 50% (from the average of the last 5 years) by 2020. Turning points in the country's dengue-control programme have been the restructuring and restrategizing of the core functions; this has involved establishment of a separate dengue-control unit to coordinate integrated vector management, and creation of a presidential task force. There has been great progress in disease surveillance, clinical management and vector control. Enhanced real-time surveillance for early warning allows ample preparedness for an outbreak. National guidelines with enhanced diagnostics have significantly improved clinical management of dengue, reducing the case-fatality rate to 0.2%. Proactive integrated vector management, with multisector partnership, has created a positive vector-control environment; however, sustaining this momentum is a challenge. Robust surveillance, evidence-based clinical management, sustainable vector control and effective communication are key strategies that will be implemented to achieve set targets. Improved early detection and a standardized treatment protocol with enhanced diagnostics at all medical care institutions will lead to further reduction in mortality. Making the maximum effort to minimize outbreaks through sustainable vector control in the three dimensions of risk mapping, innovation and risk modification will enable a reduction in morbidity.

Costing of immunization service provision in Kalutara district, Sri Lanka: a cross-sectional study.

BACKGROUND: Immunization is regarded as the single most cost-effective way to prevent vaccine-preventable diseases. With the rising cost of the National Immunization Programme (NIP) in Sri Lanka, immunization costing studies could help programme managers to ensure sustainable immunization financing in the country. METHODS: Four medical officer of health (MOH) divisions in Kalutara district were included, to estimate the cost incurred for the NIP programme. Fifteen immunization clinics from urban and rural settings were selected from the selected MOH divisions, by a simple random sampling method. Data were collected for a period of 3 months, using pretested check-lists. In addition, related data at national and district levels were also collected. Cost estimates were made for direct capital and recurrent costs. RESULTS: The cost of vaccines under the national immunization schedule for infants was 1361.84 SL Rs (US$ 10.32). For children under 5 years of age, it was 1535.64 SL Rs (US$ 11.63). The majority of these costs were direct recurrent costs (93.4%). Vaccines (84.3%) and staff salaries (6.4%) were the main components of direct recurrent costs, while cold-chain equipment (5.3%) was the main contributor to direct capital cost. CONCLUSION: The cost of vaccine is the highest proportion among all other cost components in the NIP in Sri Lanka, and this is largely attributable to new costly vaccines. Staff payments are not significant, as they are a shared cost of public health service providers. Studies exploring the costing of the NIP in the country would be beneficial, to ensure sustainable immunization financing.

Strengthening of causality assessment of adverse events following immunization in the WHO South East Asia and Western Pacific regions: Lessons from the 2014 SEAR inter-country workshop.

BACKGROUND: Poorly managed AEFI undermine immunization programs. Improved surveillance in SEAR countries means more AEFIs but management varies. SEAR brought countries together to share AEFI experiences, and learn more about causality assessment. METHODS: Three day 10 country workshop (9 SEAR; 1 WPR). Participants outlined county AEFI experiences, undertook causality assessment for 8 AEFIs using WHO methodology, critiqued the process by questionnaire and had a discussion. RESULTS: All 10 valued AEFI monitoring and causality assessment, and praised the opportunity to share experiences. Participants determined a range of AEFI and causality assessment needs in SEAR such as adapting WHO Algorithm, CIOMS/Brighton definitions, WHO verbal autopsy to fit context, requesting a practical guide--AEFI definition, time interval, rates of AEFI for different vaccines and evidence for vaccine related causes of death under 24h. CONCLUSIONS: LMIC need WHO AEFI tools adapted to better fit LMIC. Learning from each other builds capacity. Sharing AEFI experiences, case reviews help LMIC improve practices.

Burden of dengue infection and disease in a pediatric cohort in urban Sri Lanka.

Dengue is the most significant arthropod-borne viral infection of humans. Persons infected with dengue viruses (DENV) have subclinical or clinically apparent infections ranging from undifferentiated fever to dengue hemorrhagic fever/shock syndrome. Although recent studies estimated that the Indian subcontinent has the greatest burden of DENV infection and disease worldwide, we do not have reliable, population-based estimates of the incidence of infection and disease in this region. The goal of this study was to follow-up a cohort of 800 children living in a heavily urbanized area of Colombo, Sri Lanka to obtain accurate estimates of the incidence of DENV infection and disease. Annual blood samples were obtained from all children to estimate dengue seroprevalence at enrollment and to identify children exposed to new DENV infections during the study year. Blood was also obtained from any child in whom fever developed over the course of the study year to identify clinically apparent DENV infections. At enrollment, dengue seroprevalence was 53.07%, which indicated high transmission in this population. Over the study year, the incidence of DENV infection and disease were 8.39 (95% confidence interval = 6.56-10.53) and 3.38 (95% confidence interval = 2.24-4.88), respectively, per 100 children per year. The ratio of clinically inapparent to apparent infections was 1.48. These results will be useful for obtaining more accurate estimates of the burden of dengue in the region and for making decisions about testing and introduction of vaccines.

Effective vaccine safety systems in all countries: a challenge for more equitable access to immunization.

Serious vaccine-associated adverse events are rare. To further minimize their occurrence and to provide adequate care to those affected, careful monitoring of immunization programs and case management is required. Unfounded vaccine safety concerns have the potential of seriously derailing effective immunization activities. To address these issues, vaccine pharmacovigilance systems have been developed in many industrialized countries. As new vaccine products become available to prevent new diseases in various parts of the world, the demand for effective pharmacovigilance systems in low- and middle-income countries (LMIC) is increasing. To help establish such systems in all countries, WHO developed the Global Vaccine Safety Blueprint in 2011. This strategic plan is based on an in-depth analysis of the vaccine safety landscape that involved many stakeholders. This analysis reviewed existing systems and international vaccine safety activities and assessed the financial resources required to operate them. The Blueprint sets three main strategic goals to optimize the safety of vaccines through effective use of pharmacovigilance principles and methods: to ensure minimal vaccine safety capacity in all countries; to provide enhanced capacity for specific circumstances; and to establish a global support network to assist national authorities with capacity building and crisis management. In early 2012, the Global Vaccine Safety Initiative (GVSI) was launched to bring together and explore synergies among on-going vaccine safety activities. The Global Vaccine Action Plan has identified the Blueprint as its vaccine safety strategy. There is an enormous opportunity to raise awareness for vaccine safety in LMIC and to garner support from a large number of stakeholders for the GVSI between now and 2020. Synergies and resource mobilization opportunities presented by the Decade of Vaccines can enhance monitoring and response to vaccine safety issues, thereby leading to more equitable delivery of vaccines worldwide.

Dengue outbreak in Hadramout, Yemen, 2010: an epidemiological perspective.

We analyzed surveillance data of a dengue outbreak (2010) reported to the Hadramout Health Office (Yemen) and retrospectively analyzed dengue-related epidemiological and entomological events reported in Hadramout from 2005 to 2009. A total of 630 immunoglobulin M (IgM) -confirmed dengue cases of 982 febrile cases was reported during the period from February to June of 2010; 12 cases died, giving case fatality a rate of 1.9%. Among febrile cases, the highest proportion of dengue cases (37.3%) was reported in the 15- to 24-year-old age group. The overall attack rate was 0.89/1,000. The average number of cases reported by month over the preceding 5-year period compared with the 2010 data is consistent with endemicity of dengue in the region and supports epidemic designation for the dengue activity in 2010. Recognition of endemic dengue transmission and potential for substantial dengue epidemics highlight the need for consistent laboratory-based surveillance that can support prevention and control activities accordingly.

Dengue in the Middle East: a neglected, emerging disease of importance.

Dengue transmission has increased worldwide, particularly in Asia and Latin America since the 1970s, but limited information on the disease is available from the Middle East. Saudi Arabia and Yemen have reported a few epidemics of dengue. Three of the four dengue virus serotypes (DENV-1-3) have been reported in the region. Climate conditions in the Middle East are not favourable for the disease vector, but all other risk factors for dengue are potentially increasing. The existence of a large immigrant work force from dengue-endemic countries, increased travel from and to dengue-endemic countries and increased urbanization are expected to increase the likelihood of the emergence of dengue in the Middle East.