A Systematic Framework for Prioritizing Burden of Disease Data Required for Vaccine Development and Implementation: The Case for Group A Streptococcal Diseases.

Vaccine development and implementation decisions need to be guided by accurate and robust burden of disease data. We developed an innovative systematic framework outlining the properties of such data that are needed to advance vaccine development and evaluation, and prioritize research and surveillance activities. We focus on 4 objectives-advocacy, regulatory oversight and licensure, policy and post-licensure evaluation, and post-licensure financing-and identify key stakeholders and specific requirements for burden of disease data aligned with each objective. We apply this framework to group A Streptococcus, a pathogen with an underrecognized global burden, and give specific examples pertinent to 8 clinical endpoints. This dynamic framework can be adapted for any disease with a vaccine in development and can be updated as vaccine candidates progress through clinical trials. This framework will also help with research and innovation priority setting of the Immunization Agenda 2030 (IA2030) and accelerate development of future vaccines.

Antibiotic consumption for sore throat and the potential effect of a vaccine against group A Streptococcus: a systematic review and modelling study.

BACKGROUND: Antibiotic consumption can lead to antimicrobial resistance and microbiome imbalance. We sought to estimate global antibiotic consumption for sore throat, and the potential reduction in consumption due to effective vaccination against group A Streptococcus (Strep A). METHODS: We reviewed and analysed articles published between January 2000 and February 2022, identified though Clarivate Analytics' Web of Science search platform, with reference to antibiotic prescribing or consumption, sore throat, pharyngitis, or tonsillitis. We then used those analyses, combined with assumptions for the effectiveness, duration of protection, and coverage of a vaccine, to calculate the estimated reduction in antibiotic prescribing due to the introduction of Strep A vaccines. FINDINGS: We identified 101 studies covering 38 countries. The mean prescribing rate for sore throat was approximately 5 courses per 100 population per year, accounting for approximately 5% of all antibiotic consumption. Based on 2020 population estimates for countries with empiric prescribing rates, antibiotic consumption for sore throat was estimated to exceed 37 million courses annually, of which half could be attributable to treatment for Strep A. A vaccine that reduces rates of Strep A infection by 80%, with 80% coverage and 10 year's duration of protection, could avert 2.8 million courses of antibiotics prescribed for sore throat treatment among 5-14 year-olds in countries with observed prescribing rates, increasing to an estimated 7.5 million averted if an effective vaccination program also reduced precautionary prescribing. INTERPRETATION: A vaccine that prevents Strep A throat infections in children may reduce antibiotic prescribing for sore throat by 32-87% depending on changes to prescribing and consumption behaviours. FUNDING: The Wellcome Trust, grant agreement number 215490/Z/19/Z.

Harmonizing Surveillance Methodologies for Group A Streptococcal Diseases.

Group A Streptococcus (Strep A) is responsible for a significant global health and economic burden. The recent prioritization of Strep A vaccine development by the World Health Organization has prompted global research activities and collaborations. To progress this prioritization, establishment of robust surveillance for Strep A to generate updated regional disease burden estimates and to establish platforms for future impact evaluation is essential. Through the activities of the Strep A Vaccine Global Consortium (SAVAC), we have refined and harmonized surveillance protocols for 7 Strep A disease endpoints with a view that these will form part of surveillance standards for ongoing research and public health activities.

The global burden of sore throat and group A Streptococcus pharyngitis: A systematic review and meta-analysis.

Background: Contemporary data for the global burden of sore throat and group A Streptococcus (Strep A) pharyngitis are required to understand the frequency of disease and develop value propositions for Strep A vaccines. Methods: We used Clarivate Analytics' Web of Science platform to search WoS core collection, PubMed, Medline, data citation index, KCI-Korean Journal Database, Russian Science Citation Index, and the SciELO Citation Index for articles published between Jan 1, 2000, and Feb 15, 2021, from any country and in any language. The risk of bias was assessed using the JBI critical appraisal checklist. We used random-effects meta-analyses to pool sore throat and Strep A sore throat incidence rates from community-based studies. Our study was registered with PROSPERO (CRD42020181103). Findings: Of 5,529 articles identified by the search strategy, 26 studies met the inclusion criteria, but only two included data to determine incidence among adults. The pooled incidence rate, calculated for children only, was 82.2 episodes per 100 child-years (95% CI 25.2-286.3, I2 = 100%) for sore throat (7 studies; 7,964 person years) and 22.1 episodes per 100 child-years (95% CI 14.7-33.1, I2 = 98%) for Strep A sore throat (9 studies; 15,696 person years). The pooled cumulative incidence rate of sore throat from five studies was 31.9 per 100 children. There was significant methodological and statistical heterogeneity among studies, and five of 26 studies had a risk of bias score less than five (range: nine [maximum score] to one). Interpretation: Strep A sore throat has a considerable global burden. However, methodologically standardised studies are required to quantify that burden, analyse differences in rates between populations, and evaluate the likely impact of future Strep A vaccines. Funding: This study was funded by Wellcome Trust 215,490/Z/19/Z.

Standardization of Epidemiological Surveillance of Rheumatic Heart Disease.

Rheumatic heart disease (RHD) is a long-term sequela of acute rheumatic fever (ARF), which classically begins after an untreated or undertreated infection caused by Streptococcus pyogenes (Strep A). RHD develops after the heart valves are permanently damaged due to ARF. RHD remains a leading cause of morbidity and mortality in young adults in resource-limited and low- and middle-income countries. This article presents case definitions for latent, suspected, and clinical RHD for persons with and without a history of ARF, and details case classifications, including differentiating between definite or borderline according to the 2012 World Heart Federation echocardiographic diagnostic criteria. This article also covers considerations specific to RHD surveillance methodology, including discussions on echocardiographic screening, where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare), participant eligibility, and the surveillance population. Additional considerations for RHD surveillance, including implications for secondary prophylaxis and follow-up, RHD registers, community engagement, and the negative impact of surveillance, are addressed. Finally, the core elements of case report forms for RHD, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed.

Standardization of Epidemiological Surveillance of Acute Rheumatic Fever.

Acute rheumatic fever (ARF) is a multiorgan inflammatory disorder that results from the body's autoimmune response to pharyngitis or a skin infection caused by Streptococcus pyogenes (Strep A). Acute rheumatic fever mainly affects those in low- and middle-income nations, as well as in indigenous populations in wealthy nations, where initial Strep A infections may go undetected. A single episode of ARF puts a person at increased risk of developing long-term cardiac damage known as rheumatic heart disease. We present case definitions for both definite and possible ARF, including initial and recurrent episodes, according to the 2015 Jones Criteria, and we discuss current tests available to aid in the diagnosis. We outline the considerations specific to ARF surveillance methodology, including discussion on where and how to conduct active or passive surveillance (eg, early childhood centers/schools, households, primary healthcare, administrative database review), participant eligibility, and the surveillance population. Additional considerations for ARF surveillance, including implications for secondary prophylaxis and follow-up, ARF registers, community engagement, and the impact of surveillance, are addressed. Finally, the core elements of case report forms for ARF, monitoring and audit requirements, quality control and assurance, and the ethics of conducting surveillance are discussed.

Standardization of Epidemiological Surveillance of Group A Streptococcal Impetigo.

Impetigo is a highly contagious bacterial infection of the superficial layer of skin. Impetigo is caused by group A Streptococcus (Strep A) and Staphylococcus aureus, alone or in combination, with the former predominating in many tropical climates. Strep A impetigo occurs mainly in early childhood, and the burden varies worldwide. It is an acute, self-limited disease, but many children experience frequent recurrences that make it a chronic illness in some endemic settings. We present a standardized surveillance protocol including case definitions for impetigo including both active (purulent, crusted) and resolving (flat, dry) phases and discuss the current tests used to detect Strep A among persons with impetigo. Case classifications that can be applied are detailed, including differentiating between incident (new) and prevalent (existing) cases of Strep A impetigo. The type of surveillance methodology depends on the burden of impetigo in the community. Active surveillance and laboratory confirmation is the preferred method for case detection, particularly in endemic settings. Participant eligibility, surveillance population and additional considerations for surveillance of impetigo, including examination of lesions, use of photographs to document lesions, and staff training requirements (including cultural awareness), are addressed. Finally, the core elements of case report forms for impetigo are presented and guidance for recording the course and severity of impetigo provided.

Standardization of Epidemiological Surveillance of Group A Streptococcal Pharyngitis.

Pharyngitis, more commonly known as sore throat, is caused by viral and/or bacterial infections. Group A Streptococcus (Strep A) is the most common bacterial cause of pharyngitis. Strep A pharyngitis is an acute, self-limiting disease but if undertreated can lead to suppurative complications, nonsuppurative poststreptococcal immune-mediated diseases, and toxigenic presentations. We present a standardized surveillance protocol, including case definitions for pharyngitis and Strep A pharyngitis, as well as case classifications that can be used to differentiate between suspected, probable, and confirmed cases. We discuss the current tests used to detect Strep A among persons with pharyngitis, including throat culture and point-of-care tests. The type of surveillance methodology depends on the resources available and the objectives of surveillance. Active surveillance and laboratory confirmation is the preferred method for case detection. Participant eligibility, the surveillance population and additional considerations for surveillance of pharyngitis are addressed, including baseline sampling, community engagement, frequency of screening and season. Finally, we discuss the core elements of case report forms for pharyngitis and provide guidance for the recording of severity and pain associated with the course of an episode.

Standardization of Epidemiological Surveillance of Invasive Group A Streptococcal Infections.

Invasive group A streptococcal (Strep A) infections occur when Streptococcus pyogenes, also known as beta-hemolytic group A Streptococcus, invades a normally sterile site in the body. This article provides guidelines for establishing surveillance for invasive Strep A infections. The primary objective of invasive Strep A surveillance is to monitor trends in rates of infection and determine the demographic and clinical characteristics of patients with laboratory-confirmed invasive Strep A infection, the age- and sex-specific incidence in the population of a defined geographic area, trends in risk factors, and the mortality rates and rates of nonfatal sequelae caused by invasive Strep A infections. This article includes clinical descriptions followed by case definitions, based on clinical and laboratory evidence, and case classifications (confirmed or probable, if applicable) for invasive Strep A infections and for 3 Strep A syndromes: streptococcal toxic shock syndrome, necrotizing fasciitis, and pregnancy-associated Strep A infection. Considerations of the type of surveillance are also presented, noting that most people who have invasive Strep A infections will present to hospital and that invasive Strep A is a notifiable disease in some countries. Minimal surveillance necessary for invasive Strep A infection is facility-based, passive surveillance. A resource-intensive but more informative approach is active case finding of laboratory-confirmed Strep A invasive infections among a large (eg, state-wide) and well defined population. Participant eligibility, surveillance population, and additional surveillance components such as the use of International Classification of Disease diagnosis codes, follow-up, period of surveillance, seasonality, and sample size are discussed. Finally, the core data elements to be collected on case report forms are presented.

Standardization of Epidemiological Surveillance of Group A Streptococcal Cellulitis.

Cellulitis is an acute bacterial infection of the dermis and subcutaneous tissue usually found complicating a wound, ulcer, or dermatosis. This article provides guidelines for the surveillance of cellulitis. The primary objectives of cellulitis surveillance are to (1) monitor trends in rates of infection, (2) describe the demographic and clinical characteristics of patients with cellulitis, (3) estimate the frequency of complications, and (4) describe the risk factors associated with primary and recurrent cellulitis. This article includes case definitions for clinical cellulitis and group A streptococcal cellulitis, based on clinical and laboratory evidence, and case classifications for an initial and recurrent case. It is expected that surveillance for cellulitis will be for all-cause cellulitis, rather than specifically for Strep A cellulitis. Considerations of the type of surveillance are also presented, including identification of data sources and surveillance type. Minimal surveillance necessary for cellulitis is facility-based, passive surveillance. Prospective, active, facility-based surveillance is recommended for estimates of pathogen-specific cellulitis burden. Participant eligibility, surveillance population, and additional surveillance considerations such as active follow-up of cases, the use of International Classification of Disease diagnosis codes, and microbiological sampling of cases are discussed. Finally, the core data elements to be collected on case report forms are presented.

Standardization of Epidemiological Surveillance of Acute Poststreptococcal Glomerulonephritis.

Acute poststreptococcal glomerulonephritis (APSGN) is an immune complex-induced glomerulonephritis that develops as a sequela of streptococcal infections. This article provides guidelines for the surveillance of APSGN due to group A Streptococcus (Strep A). The primary objectives of APSGN surveillance are to monitor trends in age- and sex-specific incidence, describe the demographic and clinical characteristics of patients with APSGN, document accompanying risk factors, then monitor trends in frequency of complications, illness duration, hospitalization rates, and mortality. This document provides surveillance case definitions for APSGN, including clinical and subclinical APSGN based on clinical and laboratory evidence. It also details case classifications that can be used to differentiate between confirmed and probable cases, and it discusses the current investigations used to provide evidence of antecedent Strep A infection. The type of surveillance recommended depends on the burden of APSGN in the community and the objectives of surveillance. Strategies for minimal surveillance and enhanced surveillance of APSGN are provided. Furthermore, a discussion covers the surveillance population and additional APSGN-specific surveillance considerations such as contact testing, active follow up of cases and contacts, frequency of reporting, surveillance visits, period of surveillance, and community engagement. Finally, the document presents core data elements to be collected on case report forms, along with guidance for documenting the course and severity of APSGN.

Higher ultraviolet radiation during early life is associated with lower risk of childhood type 1 diabetes among boys.

Population-level ecological studies show type 1 diabetes incidence is inversely correlated with ambient ultraviolet radiation (UVR) levels. We conducted a nested case-control study using administrative datasets to test this association at the individual level. Cases (n = 1819) were children born in Western Australia (WA) from 1980-2014, diagnosed with type 1 diabetes at ≤ 16 years. Controls (n = 27,259) were randomly selected from all live births in WA, matched to cases by sex and date of birth. Total ambient erythemal ultraviolet radiation (UVR) doses for each trimester of pregnancy and first year of life were estimated for each individual, using daily NASA satellite data that were date- and geographically-specific. Conditional logistic regression tested the association between UVR dose and case-control status. Type 1 diabetes risk was 42% lower in boys of mothers with third-trimester UVR dose in the highest (compared to the lowest) quartile (p = 0.04). Higher UVR in the first year of life was associated with lower type 1 diabetes risk among boys (p = 0.01). UVR dose was not associated with type 1 diabetes risk in girls. Higher UVR in late pregnancy and early life appear to interact with sex-specific factors to lower type 1 diabetes risk among boys in Western Australia.

Demographic and clinical predictors of vitamin D status in pregnant women tested for deficiency in Western Australia.

OBJECTIVE: This study aimed to describe the vitamin D status of pregnant women in Western Australia and identify predictors of deficiency in pregnancy. METHODS: A cross-sectional study was conducted using linked data from statewide administrative data collections. Participants included pregnant women aged 18-44 years who gave birth between 2012 and 2014. RESULTS: The mean 25-hydroxyvitamin D (25[OH]D) concentration was 70.7 nmol L-1 (SD 25.7; range 5-255 nmol L-1 ). Approximately one-fifth of the pregnant women were vitamin D deficient (<50 nmol L-1 ). Maternal age (under 25 years) was identified as an independent risk factor of vitamin D deficiency in addition to known predictors. Only 20% of women were screened within the first 10 weeks of their pregnancy. CONCLUSIONS: In addition to the existing risk factors for deficiency, maternal age was an independent predictor of vitamin D deficiency. There was a large discrepancy between the time of first antenatal visit and screening for vitamin D deficiency. Implications for public health: Our findings support the addition of maternal age (under 25 years) to the current clinical guidelines for targeted screening of 25(OH)D levels in pregnancy and the practical application of screening for vitamin D deficiency at the first antenatal visit.

Use of linked administrative and laboratory data to confirm that serum 25(OH)D levels in pregnant women can be predicted from satellite estimates of ultraviolet radiation.

BACKGROUND: Serum 25 hydroxyvitamin D [25(OH)D] levels of pregnant women have been linked to various health outcomes in their offspring. Satellite-derived ultraviolet radiation (UVR) data have been used as a proxy for 25(OH)D levels, as individual-level cohort studies are time-consuming, costly and only feasible for common outcomes. METHODS: Data on 25(OH)D levels from a public laboratory database were linked to data from the Western Australian Midwives' Notification System and daily erythemal UVR dose from NASA satellites. Regression analysis was used to identify the time period prior to venesection where daily UVR dose best predicted 25(OH)D levels. A predictive model was used to validate the use of daily UVR dose as a proxy for personal sun exposure during pregnancy. RESULTS: Data from 19 173 pregnancies in women aged 18-43 years in Western Australia were included. The daily UVR dose averaged over the 90 days before venesection was the strongest UVR predictor of 25(OH)D level (a 5% increase per 1000 J m-2; equal to 3.3 nmol L-1 at the median of 66 nmol L-1). Ethnicity was the strongest predictor of 25(OH)D levels (21% lower in non-Caucasian vs Caucasian: equal to 7.2 nmol L-1 difference). Other significant predictors were gestation, age, year, parity, socio-economic status, remoteness, medical conditions and season. CONCLUSION: NASA-derived erythemal UVR dose in the 90 days prior to venesection is a significant predictor of 25(OH)D levels in pregnant women. Linked administrative data can be used to investigate associations between UVR during pregnancy and health outcomes in offspring.