Learning from the COVID-19 pandemic to strengthen routine immunization systems

Kate Causey and Jonathan F Mosser discuss what can be learnt from the observed impacts of the COVID-19 pandemic on routine immunisation systems.

In the final months of 2021, deaths due to the Coronavirus Disease 2019 (COVID-19) surpassed 5 million globally [1]. Available data suggest that even this staggering figure may be a substantial underestimate of the true toll of the pandemic [2]. Beyond mortality, it may take years to fully quantify the direct and indirect impacts of the COVID-19 pandemic such as disruptions in preventive care services. In an accompanying research study in PLOS Medicine, McQuaid and colleagues report on the uptake of routine childhood immunizations in 2020 in Scotland and England during major pandemic-related lockdowns [3]. This adds to a growing body of literature quantifying the impact of the COVID-19 pandemic on routine health services and childhood immunization [4,5], which provides important opportunities to learn from early pandemic experiences as immunization systems face ongoing challenges.McQuaid and colleagues compared weekly or monthly data on vaccine uptake in Scotland and England from January to December of 2020 to the rates observed in 2019 to estimate the changes in uptake before, during, and after COVID-19 pandemic lockdowns in each country. The authors included 2 different preschool immunizations, each with multiple doses. They found significantly increased uptake within 4 weeks of eligibility during the lockdown and postlockdown periods in Scotland for all 5 vaccine dose combinations examined: During lockdown, percentage point increases ranged from 1.3% to 14.3%. In England, there were significant declines in uptake during the prelockdown, lockdown, and postlockdown periods for all 4 vaccine dose combinations examined. However, declines during lockdown were small, with percentage point decreases ranging from −0.5% to −2.1%. Due to the nature of the data available, the authors were unable to account for possible seasonal variation in vaccine delivery, control for important individual-level confounders or effect modifiers such as child sex and parental educational attainment, or directly compare outcomes across the 2 countries.These findings stand in contrast to the documented experience of many other countries, where available data suggest historic disruptions in routine childhood vaccination coverage, particularly during the first months of pandemic-related lockdowns [5,6]. Supply side limitations such as delayed shipments of vaccines and supplies [7], inadequate personal protective equipment [8], staff shortages [9], and delayed or canceled campaigns and introductions [9] threatened vaccine delivery. Furthermore, fear of exposure to COVID-19 at vaccination centers [10], misinformation about vaccine safety [8], and lockdown-related limitations on travel to facilities [9,10] reduced demand. In polls of country experts conducted by WHO, UNICEF, and Gavi, the Vaccine Alliance throughout the second quarter of 2020, 126 of 170 countries reported at least some disruption to routine immunization programs [10,11]. Global estimates suggest that millions more children missed doses of important vaccines than would have in the absence of the COVID-19 pandemic [5,6]. While many vaccine programs showed remarkable resilience in the second half of 2020, with rates of vaccination returning to or even exceeding prepandemic levels [5,6], disruptions to immunization services persisted into 2021 in many countries [12].As the authors discuss, it is critical to pinpoint the specific program policies and strategies that contributed to increased uptake in Scotland and only small declines in England and, more broadly, to the rapid recovery of vaccination rates observed in many other countries. McQuaid and colleagues cite work suggesting that increased flexibility in parental working patterns during lockdowns, providing mobile services or public transport to vaccine centers, and sending phone- and mail-based reminders are strategies that may have improved uptake of timely vaccination in Scotland during this period [13]. Similarly, immunization programs around the world have employed a broad range of strategies to maintain or increase vaccination during the pandemic. Leaders in Senegal, Paraguay, and Sri Lanka designed and conducted media campaigns to emphasize the importance of childhood immunization even during lockdown [8,14,15]. Although many programs delayed mass campaigns in the spring of 2020, multiple countries were able to implement campaigns by the summer of 2020 [8,16–20]. In each of these examples, leaders responded quickly to meet the unique challenges presented by the COVID-19 pandemic in their communities.Increased data collection and tracking systems are essential for efficient and effective responses as delivery programs face challenges. When concern arose for pandemic-related disruptions to immunization services, public health decision-makers in Scotland and England responded by increasing the frequency and level of detail in reports of vaccine uptake and by making these data available for planning and research. The potential for robust data systems to inform real-time decision-making is not limited to high-income countries. For instance, the Nigerian National Health Management Information System released an extensive online dashboard shortly after the onset of the pandemic, documenting the impact of COVID-19 on dozens of indicators of health service uptake, including 16 related to immunization [21]. Vaccination data systems that track individual children and doses, such as the reminder system in Scotland, allow for highly targeted responses. Similarly, in Senegal, Ghana, and in Karachi, Pakistan, healthcare workers have relied on existing or newly implemented tracking systems to identify children who have missed doses and provide text message and/or phone call reminders [8,22,23]. Investing in robust routine data systems allows for rapid scale-up of data collection, targeted services to those who miss doses, and a more informed response when vaccine delivery challenges arise.Policy and program decision-makers must learn from the observed impacts of the COVID-19 pandemic on health systems and vaccine delivery. The study by McQuaid and colleagues provides further evidence that vaccination programs in England and Scotland leveraged existing strengths and identified novel strategies to mitigate disruptions and deliver vaccines in the early stages of the pandemic. However, the challenges posed by the pandemic to routine immunization services continue. To mitigate the risk of outbreaks of measles and other vaccine-preventable diseases, strategies are needed to maintain and increase coverage, while ensuring that children who missed vaccines during the pandemic are quickly caught up. The accompanying research study provides important insights into 2 countries where services were preserved—and even increased—in the early pandemic. To meet present and future challenges, we must learn from early pandemic successes such as those in Scotland and England, tailor solutions to improve vaccine uptake, and strengthen data systems to support improved decision-making.     

Tuberculosis preventive treatment in people living with HIV—Is the glass half empty or half full?

Olivia Oxlade and co-authors introduce a Collection on tuberculosis preventive therapy in people with HIV infection.

The most recent World Health Organization Global Tuberculosis (TB) Report suggests that 50% of people living with HIV (PLHIV) newly enrolled in HIV care initiated tuberculosis preventive treatment (TPT) in 2019 [1]. TPT is an essential intervention to prevent TB disease among people infected with Mycobacterium tuberculosis—some 25% of the world’s population [2]. Without TPT, it is estimated that up to 10% of individuals will progress to TB disease. Among PLHIV, the prognosis is worse. Of the approximately 1.4 million annual deaths from TB, 200,000 occur among PLHIV [1], who experience TB at rates more than 30 times [3] higher than people living without HIV.In 2018, governments at the United Nations High-Level Meeting (UNHLM) on TB committed to rapid expansion of testing for TB infection and provision of TPT [4]. The goal was the provision of TPT to at least 24 million household contacts of people with TB disease and 6 million PLHIV between 2018 and 2022. However, by the end of 2019, fewer than half a million household contacts had initiated TPT, well short of the pace needed to achieve the 5-year target [1]. On the other hand, approximately 5.3 million PLHIV have initiated TPT in the past 2 years [1], with particularly dramatic increases in countries supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) [5]. Globally, among PLHIV entering HIV care programs, TPT initiation rose from 36% in 2017 to 49% in 2018 and 50% in 2019 [6,7].To provide insight into scaling up TPT for PLHIV, it is important to consider each of the many steps involved in the “cascade of care” for TPT. A previous systematic review of studies in several populations receiving TPT concluded that nearly 70% of all people who may benefit from TPT were lost to follow-up at cascade of care steps prior to treatment initiation [8]. To maximize the impact of TPT for TB prevention among PLHIV, the full TPT cascade of care must be assessed to identify problems and develop targeted solutions addressing barriers at each step. Until now, these data had not been synthesized for PLHIV.In order to address important research gaps related to TPT in PLHIV such as this one, we are now presenting a Collection in PLOS Medicine on TPT in PLHIV. In the first paper in this Collection, Bastos and colleagues performed a systematic review and meta-analysis of the TPT cascade of care in 71 cohorts with a total of 94,011 PLHIV [9]. This analysis highlights key steps in the cascade where substantial attrition occurs and identifies individual-level and programmatic barriers and facilitators at each step. In stratified analyses, they found that losses during the TPT cascade were not different in high-income compared to low- or middle-income settings, nor were losses greater in centers performing tests for TB infection (tuberculin skin test [TST] or interferon gamma release assay [IGRA]) prior to TPT initiation.The net benefits of TPT could potentially be increased through greater adoption of shorter rifamycin-based TPT regimens, for which there is increasing evidence of greater safety, improved treatment completion, and noninferior efficacy, compared to isoniazid regimens. Two reviews of rifamycin-based regimens in mostly HIV–negative adults and children concluded that they were as effective for prevention of TB as longer isoniazid-based regimens, with better treatment completion and fewer adverse events [10,11]. However, safety and tolerability of TPT regimens can differ substantially between people with and without HIV, and for rifamycin-based TPT regimens, safety outcomes were actually worse in people without HIV [12], plus there can be important drug–drug interactions between rifamycin-based regimens and antiretroviral drugs [13]. Reviews of studies focused on PLHIV concluded that TPT (regardless of regimen selected) significantly reduced TB incidence [14] and that the benefits of continuous isoniazid in high TB transmission settings outweighed the risks [15]. As part of this Collection, Yanes-Lane and colleagues conducted a systematic review and network meta-analysis of 16 randomized trials to directly and indirectly compare the risks and benefits of isoniazid and rifamycin-based TPT regimens among PLHIV [16]. Their findings highlight the better safety, improved completion, and evidence of efficacy, particularly reduced mortality, with rifamycin-based TPT regimens, while also noting improved TB prevention with extended duration mono-isoniazid regimens. Their review also revealed that few studies exist on some important at-risk populations, such was pregnant women and those with drug-resistant TB infection.In North America, recommendations changed in 2020 to favor shorter rifamycin-based regimens over isoniazid [17], but WHO still favors isoniazid [18], largely due to the lower drug costs. Although drug costs for rifamycins are typically higher than for isoniazid, their shorter duration and better safety profile mean that total costs for care (including personnel costs) may be lower for rifamycin-based regimens, even in underresourced settings [19]. The cost-effectiveness of different TPT regimens among PLHIV in underresourced settings remains uncertain, as well as the impact of antiretroviral therapy (ART), and the use of diagnostic tests for TB infection, such as TST or IGRA on cost efficiency. Uppal and colleagues, in the third paper in this Collection, performed a systematic review and meta-analysis of 61 published cost-effectiveness and transmission modeling studies of TPT among PLHIV [20]. In all studies, TPT was consistently cost-effective, if not cost saving, despite wide variation in key input parameters and settings considered.When comparing access to TPT among PLHIV to household contacts, many would consider the glass is half full, given that almost half of all PLHIV newly accessing care initiated TPT in 2018 and 2019, and the UNHLM goal of 6 million PLHIV initiating TPT was already nearly achieved by the end of 2020. This remarkable achievement is the result of strong recommendations from WHO for TPT among PLHIV for nearly a decade and strong donor support. These policies are, in turn, based on clear and consistent evidence of individual benefits from multiple randomized trials, plus consistent evidence of cost-effectiveness from many economic analyses as summarized in the papers in this Collection. These are useful lessons for scaling up TPT for other target populations, particularly household contacts, of whom less than half a million have initiated TPT, of the 24 million–person target set in 2018.However, the glass of TPT among PLHIV is also half empty. In contrast to the “90-90-90” targets, 50% of PLHIV newly enrolled in care do not initiate TPT, and PLHIV still bear a disproportionate burden of TB. Programmatic scale-up of TPT continues to encounter challenges that need to be overcome in order to translate individual-level success to population-level improvement. The study by Bastos and colleagues in this Collection has identified programmatic barriers including drug stockouts and suboptimal training for healthcare workers, but it also offers useful solutions, including integration of HIV and TPT services [9]. New evidence on the success of differentiated service delivery will also be invaluable to support programmatic scale-up in different settings [21]. Acting on this evidence will be essential to achieve the goal of full access to effective, safe, and cost-effective TPT for PLHIV.     

Estimating lifetime risk of diabetes in the Chinese population

In this Perspective, Fiona Bragg and Zhengming Chen discuss the burden of diabetes in the Chinese Population.

The worldwide epidemic of diabetes continues to grow [1]. In China, the rise in prevalence has been notably rapid; about 12% of the adult population has diabetes [2], accounting for almost one quarter of cases worldwide [1] and representing a 10-fold increase over the last 3 to 4 decades. It is appropriate, therefore, that diabetes—both prevention and management—is a major focus of current health policy initiatives in China [3,4], and their success depends on reliable quantification of the burden of diabetes. Commonly used measures such as prevalence and incidence fail to capture excess mortality risks or differences in life expectancy in diabetes [5]. Moreover, they may be less easily interpreted by policy makers and affected individuals. Estimates of lifetime risks and life years spent living with diabetes in an accompanying study by Luk and colleagues provide a valuable new perspective on the burden of diabetes in the Chinese population [6].The study used Hong Kong territory-wide electronic health records data for 2.6 million adults. Using a Markov chain model and Monte-Carlo simulations, Luk and colleagues estimated age- and sex-specific lifetime risks of diabetes (incorporating both clinically diagnosed and undiagnosed diabetes) and remaining life years spent with diabetes. Their findings showed a lifetime risk of 65.9% and 12.7 years of life living with diabetes for an average 20-year old with normoglycaemia. For an average 20-year old with prediabetes the corresponding estimates were 88.0% and 32.5 years, respectively. In other words, 6 out of 10 20-year olds with normoglycaemia and 9 out of 10 with prediabetes would be expected to develop diabetes in their lifetime. The estimated lifetime risks declined with increasing age and were higher among women than men at all ages, likely reflecting women’s higher life expectancy.These estimated lifetime risks are striking and concerning. Moreover, they are notably higher than western population estimates [7–10], including those considering both diagnosed and undiagnosed diabetes [9,10]. An Australian study estimated that 38% of 25-year olds would develop diabetes in their lifetime [10]. Another study in the Netherlands reported 31.3% and 74.0% probabilities of developing diabetes in the remaining lifetime for individuals aged 45 years without diabetes and with prediabetes, respectively [9]. Diabetes incidence and overall mortality influence population lifetime risks. Differences in the glycaemic indicators used to identify undiagnosed diabetes may have contributed to differences between studies in diabetes incidence. In the study by Luk and colleagues, a combination of fasting plasma glucose (FPG), HbA1c levels and oral glucose tolerance testing (OGTT) was used, while in the Australian [10] and the Netherlands [9] studies, they used FPG/OGTT and mainly FPG, respectively. However, it is unlikely these differences would fully account for the large disparities seen in lifetime risk. Similarly, differences between life expectancy in Hong Kong (84.8 years), Australia (83.4 years), and the Netherlands (82.2 years) are too small to explain the differences. Interestingly, the high lifetime risks observed in Hong Kong were more comparable to those in the Indian population, estimated at 55.5% and 64.6%, respectively, among 20-year-old men and women [11]. The typical type 2 diabetes (T2D) phenotype in these Asian populations may partly explain their higher estimated lifetime risks. More specifically, T2D in both Chinese and Indian populations is characterised by onset among younger and less adipose individuals than typically observed in western populations, exacerbated by rapid urbanisation and associated unhealthy lifestyles [12].However, aspects of Luk and colleagues’ study design may have overestimated lifetime diabetes risks. Chief among these is the data source used and associated selection bias. The Hong Kong Diabetes Surveillance Database includes only individuals who have ever had a plasma glucose or HbA1c measurement undertaken in a local health authority facility. Since measurement of glycaemic indicators is more likely among individuals at greater current or future risk of dysglycaemic states, this will have inflated estimates of lifetime risk and life years spent with diabetes. Although replication was undertaken by the study authors to address this bias in the smaller China Health and Retirement Longitudinal Survey (CHARLS) cohort, it does not fully allay these concerns, with modestly lower estimated lifetime diabetes risks in the CHARLS cohort, even after accounting for its higher mortality. A further limitation is their consideration of transition to dysglycaemic states as irreversible. Although data on long-term transition between glycaemic states are lacking, reversion from prediabetes (and less commonly diabetes) to normoglycaemia is well recognised, e.g., through lifestyle interventions [13].Large-scale population-based cohort studies could valuably address many of the limitations described [14]. Furthermore, lifetime risks are, by definition, population-based and represent the risk of an average person in the population, limiting their value for communicating long-term disease risks to specific individuals. However, the extensive phenotyping (e.g., adiposity) characteristic of many large contemporary cohorts [14] would facilitate incorporation of risk factors into lifetime risk estimates, enhancing their relevance to individuals. Previous studies have found greater lifetime risks of diabetes associated with adiposity [9,11], and this approach could be extended to incorporate other established, as well as more novel (e.g., genetic), risk factors. This is arguably of particular relevance to later-onset chronic conditions, such as T2D, in which changes in risk factors during middle age can influence lifetime risks. A valuable extension of Luk and colleagues’ study will be estimation of risk factor specific lifetime diabetes risks for the Chinese population.Importantly, the limitations described do not detract from the enormity and importance of the challenge diabetes poses for China, including Hong Kong, and the estimates presented by Luk and colleagues provide valuable impetus for action. The disease burden insights can inform treatment programmes and enhance understanding of current and future impacts of diabetes and associated complications on the healthcare system. Moreover, T2D is preventable, and arguably, the greatest value of these estimated lifetime risks is in highlighting the need for, and informing the planning and provision of, diabetes primary prevention programmes. This includes identification of high-risk individuals, such as those with prediabetes, who are most likely to benefit from prevention interventions. However, the magnitude of the estimated lifetime diabetes risks, including among the large proportion of the population in a normoglycaemic state, additionally demonstrates the need for population-level prevention approaches, including environmental, structural, and fiscal strategies. Without such actions, the individual and societal consequences of diabetes for present and future generations in Hong Kong, as well as mainland China, will be immense.     

Optimizing prevention and community-based management of severe malnutrition in children

Zulfiqar A. Bhutta discusses prevention and treatment strategies for optimization of community-based management of severe acute malnutrition in children.

In this issue of PLOS Medicine, Matt Hitchings and colleagues detail the findings from their prospective cluster-randomized crossover trial conducted across 10 health centers in Sokoto, Nigeria, to assess the nutritional recovery in children with uncomplicated severe acute malnutrition (SAM) receiving monthly follow-up compared to the standard weekly follow-up schedules [1]. In almost 4,000 children so allocated, the nutritional recovery at 3 months’ follow-up was lower in the monthly follow-up group (52.4%) compared to the standard weekly group (58.8%), with higher cumulative mortality at 3 months (8.5% versus 6.2% with the standard weekly follow-up). In contrast, rates of default and relapse were significantly lower among SAM children allocated to monthly follow-up. The authors, while urging caution in adopting a modified schedule of monthly follow-up visits in such children, also recognize the trade-off of simplicity and ease of operations in some settings where weekly follow-up visits are not feasible.Despite global progress in improving maternal and child undernutrition, the high burden of severe malnutrition persists. Recent estimates show a small reduction (from 15.9% to 14.2%) in wasting prevalence in low-income countries, and a slight increase (from 3.3% to 4.7%) in middle-income countries, although overall almost 50 million children aged under 5 years still remain wasted worldwide [2]. This burden of SAM has most likely been exacerbated during the recent Coronavirus Disease 2019 (COVID-19) pandemic, with an estimated additional 6.7 million children becoming wasted in 2020 [3].Within this large number of wasted children are those with SAM who are triaged to facility-based nutritional rehabilitation if seriously ill, or community-based treatment regimens if stable. The development of standardized management protocols for children with SAM with ready-to-use therapeutic foods (RUTFs) represents one of the greatest advances in treating such children at scale and reducing the mortality associated with the condition [4]. However, given the general context where childhood SAM clusters, such as those affected by extreme poverty, climate change, conflict, and involving displaced populations, major challenges remain in optimizing SAM management. These include relatively high rates of relapse [5], and associated residual mortality with severe malnutrition, often exceeding 10% in some settings [6]. Strategies are thus needed to optimize community case management aimed at simplifying the treatment regimen for SAM, reducing defaults and relapse rates among affected children.Such real-life evaluations of management strategies for severe malnutrition among at-risk children are few and far between, and most welcome. The global evidence base for the management of SAM in various settings is still mixed, with wide variations in recovery or relapse rates and mortality. This is especially the case in complex emergencies and conflict settings [7] with obvious limitations of human resources and commodities. The challenges of managing SAM in different contexts and settings are directly related to available nutrition rehabilitation commodities and trained human resources, as well as the ability of poor and food-insecure households to follow complex regimen and follow-up schedules. For many poor households with daily wage laborers or workers, taking a day off to travel to ambulatory care settings is a weekly financial and logistic hardship that may be impossible to bear. Alternative approaches with community outreach workers providing care and commodities in domiciliary settings has also met with mixed success, with lower rates of uptake in effectiveness settings with busy public-sector workers [8,9].There are additional research questions related to the nutritional rehabilitation and management of SAM including dosage schedules and protocols for administering RUTF in outreach and ambulatory programs. Additional therapeutic challenges in managing children with SAM include the limited repertoire of options for interventions in children under 6 months of age, as well as strategies to manage children with concurrent stunting and wasting [1,10]. While the recommendations for facility-based management of unstable children with SAM are well recognized [11], corresponding protocols for ambulatory management of severely malnourished children with suspected infections and at risk of adverse outcomes are still a subject of much debate [12].The gains from potentially simplifying ambulatory management strategies for SAM are considerable but must be weighed against the best-possible and cost-effective strategies. Of great priority are strategies that integrate SAM management in community settings with additional child health and development interventions [13]. Given the close correlation and relationship between various forms of malnutrition (moderate and severe acute malnutrition), there is growing interest in common management protocols and simplified regimens for preventing and managing all forms of acute malnutrition. The sizeable subgroup of children with concurrent wasting and stunting represents a subgroup at much greater risk of adverse outcomes and mortality [14] and needs strategies that also integrate maternal and early child health and nutrition strategies.There has been a healthy increase in research related to prevention and management strategies for SAM in recent years, all adding to the evidence base for effective implementation in field settings. Corresponding processes for guidelines development by WHO are understandably cautious, but it is worth noting that the guidelines for the management of SAM by WHO are now almost a decade old [15] and need updating as well as flexibility in implementation. Studies such as those by Hitchings and colleagues [1] should show the way to optimize the screening and management of SAM in settings with limited facilities and community capacity for weekly follow-up. The recognition that such infants may be at higher risk of relapse or mortality could well require additional contacts, such as fortnightly follow-up or outreach services, areas that should be studied in future evaluations.     

Rebalancing the marketing of healthier versus less healthy food products

Jean Adams discusses the evidence around food marketing restrictions and how they may be an effective way to support public health.

We live in a world increasingly saturated with marketing for less healthy foods [1]. One study found that children in New Zealand see an average of 27 instances of marketing for less healthy foods and only 12 for healthier foods, each day [2]. Food marketing involves activities across the 4 Ps of the marketing mix: product, place, price, and promotion. We are encouraged to buy less healthy food products through their placement in prominent store locations such as checkouts, end of aisles, and store entrances; price discounts; and promotions including advertising, cartoon tie-ins, and celebrity endorsements.Systematic reviews have confirmed the effectiveness of these marketing techniques to influence purchasing and consumption of less healthy foods [3–5]. Indeed, the documented power of food marketing has led the World Health Organisation to recommended limiting exposure as an overarching and enabling “best buy” to improve diets [6].Supermarkets remain the location of about 70% of food spend in the United Kingdom [7]. The concentration of food marketing in grocery stores can feel particularly overwhelming with parents describing the “temptation” as “like a trip to the zoo every week” for their children [8]. As such, supermarkets may be particularly important venues for addressing food marketing.In 2 accompanying Research Articles in PLOS Medicine, Piernas and colleagues used nonrandomised approaches to study the impacts on sales of a range of strategies to rebalance the marketing of healthier versus less healthy products in 3 large UK supermarket chains [9,10]. Across the 2 papers, 7 different interventions were implemented that changed the relative availability of healthier versus less healthy products (2 interventions), removed less healthy products from prominent positions, placed healthier products at eye level, offered price discounts on healthier products, increased signage on healthier products, and applied a range of entertainment tie-in promotions on healthier products (one intervention each). These variously had the intention to encourage substitution of less healthy products with healthier alternatives or to reduce purchasing of less healthy foods without substitution.Increasing the relative availability of healthier products, removing less healthy products from prominent positions and price promotions on healthier products were all associated with changes in unit sales in the expected direction, although associations with changes in nutrients purchased were sometimes more modest. In contrast, moving healthier products to eye level and increasing signage were not associated with changes in sales. These findings are particularly timely in England where a range of measures to reduce exposure to marketing of less healthy foods in retail environments are due to be implemented from October 2022 [11].Piernas and colleagues worked in collaboration with large UK supermarket chains. That the chains were prepared to innovate to support public health indicates that rebalancing marketing towards healthier products may not be as burdensome to the sector as it has sometimes claimed [12]. It also strengthens the external validity of these studies giving an indication of how customers react in real-world environments.However, that the supermarket chains decided what the interventions should be also imposes limitations on wider interpretation of the findings. Each of the 7 different interventions applied to different categories of foods without any rationale made explicit to the research team—for example, chocolate confectionary was removed from prominent positions, higher fibre breakfast cereals were placed at eye level, and price discounts were applied to fruit and vegetables. This makes it hard to determine whether observed impacts were unique to specific combinations of intervention and food category. Indeed, rather than particular marketing interventions being more effective than others across the board, it is possible that complex interplays between food category, marketing intervention, and other contextual aspects (such as shop and customer characteristics) interact to produce changes in sales.The “squeezed balloon effect” proposes that restrictions on specific aspects of marketing may lead to compensatory increases in others [13]. For example, restricting television advertising of less healthy foods during and around children’s programmes in the UK was associated with increased exposure of adults to these adverts [14]. Wider compensation between, as well as within, media (for example, TV restrictions leading to more online marketing) may also be expected. It is possible that supermarkets willing to engage in university-assessed marketing changes may have self-policed any simultaneous compensatory activities, and, anyway, these would not necessarily have been identified in the studies by Piernas and colleagues. Any real-life compensation as the whole grocery sector adapts to government-imposed marketing restrictions may be difficult to predict. This reinforces the need for postimplementation evaluation.The squeezed balloon effect means that the most effective marketing restrictions may be those that target marketing of the same products through multiple simultaneous interventions. In Chile, near-simultaneous implementation of front-of-pack warning labels, advertising restrictions, and a prohibition of sales in schools of products high in calories, sodium, sugar, or saturated fat were associated with substantial declines in purchases of targeted foods and nutrients [15]. This approach is also the underlying strategy in England where near-simultaneous restrictions on TV and online advertising of less healthy foods are planned for the whole of the UK alongside the England-specific bans on location and price-based promotions [16].Despite the innovative approach in England, neither the regulations on TV and online advertising of less healthy foods nor on price and location-based promotions of these foods have cleared the parliamentary process. The UK government recently accepted an amendment to the TV and online advertising restrictions to give the Secretary of State for Health and Social Care power to delay implementation [17]. The restrictions on price and location-based promotions may be under threat of being dropped altogether [18].Piernas and colleagues’ studies add to the accumulating evidence that restricting marketing on less healthy foods and encouraging marketing on healthier foods may be an effective way to support public health. Theory and a range of evidence suggest that simultaneous restrictions on a variety of different types of less healthy food marketing are likely to be the most effective ways of reducing exposure to this marketing. The UK government has proposed this approach in England on a number of occasions. That implementation continues to hang in the balance is a sad indictment of our collective inability to create a world that supports everyone to eat in the way they want to, rather than the way the marketers want for us.     

Achieving global equity for COVID-19 vaccines: Stronger international partnerships and greater advocacy and solidarity are needed

Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.

Many may not be aware of the full extent of global inequity in the rollout of Coronavirus Disease 2019 (COVID-19) vaccines in response to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. As of June 20, 2021, only 0.9% of those living in low-income countries and less than 10% of those in low- and middle-income countries (LMICs) had received at least 1 dose of a COVID-19 vaccine compared with 43% of the population living in high-income countries (HICs) [1] (Fig 1). Only 2.4% of the population of Africa had been vaccinated compared with 41% of North America and 38% of Europe [1,2] (S1 Fig). Primarily due to the inability to access COVID-19 vaccines, less than 10% of the population in as many as 85 LMICs had been vaccinated compared with over 60% of the population in 26 HICs [1]. Only 10 countries account for more than 75% of all COVID-19 vaccines administered [3]. This striking and ongoing inequity has occurred despite the explicit ethical principles affirming equity of access to COVID-19 vaccines articulated in WHO SAGE values framework [4,5] prepared in mid-2020, well prior to the availability of COVID-19 vaccines.Open in a separate windowFig 1Proportion of people vaccinated with at least 1 dose of COVID-19 vaccine by income (April 14 to June 23, 2021).Note: Data on China appeared on the database on June 9, hence the jump in upper middle-income countries. COVID-19, Coronavirus Disease 2019. Source: https://ourworldindata.org/covid-vaccinations.The COVID-19 pandemic highlights the grave inequity and inadequacy of the global preparedness and response to serious emerging infections. The establishment of the Coalition for Epidemic Preparedness Innovations (CEPI) in 2018, the Access to COVID-19 Tools Accelerator (ACT-A), and the COVID-19 Vaccines Global Access (COVAX) Facility in April 2020 and the rapid development of COVID-19 vaccines were all positive and extraordinary developments [6]. The COVAX Facility, as of June 2021, has delivered approximately 83 million vaccine doses to 75 countries, representing approximately 4% of the global supply, and one-fifth of this was for HICs [7]. The COVAX Facility has been challenged to meet its supply commitments to LMICs due to insufficient access to doses of COVID-19 vaccines with the prerequisite WHO emergency use listing (EUL) or, under exceptional circumstances, product approval by a stringent regulatory authority (SRA) [8,9]. Because of the anticipated insufficient COVID-19 vaccine supply through the COVAX Facility, the majority of nonvaccine-producing LMIC countries made the decision, early in the COVID-19 pandemic, to secure and use vaccines produced in China or Russia prior to receipt of WHO EUL or SRA approval. Most of the vaccines used in LMICs as of June 20, 2021 (nearly 1.5 billion doses of the 2.6 billion doses administered) were neither WHO EUL or SRA approved at the time they were given [10]. This may raise possible concerns with respect to the effectiveness, safety, and acceptability of individual vaccines used by many countries [8,9].     

Investigating barriers to the protective efficacy provided by rotavirus vaccines in African infants

Julie Bines discusses an accompanying study by Sheila Isanaka and colleagues on nutrient supplementation and immune responses to rotavirus vaccination.

The introduction of rotavirus vaccines into the national immunization programs globally has made a major impact on diarrhea-related hospitalizations and deaths. By 2020, 107 countries had introduced rotavirus vaccines, either nationally or regionally, including 52 countries in Africa and Asia eligible for funding through the Global Alliance for Vaccines and Immunization (Gavi) [1]. This represents a major step toward reducing under 5-year child mortality, the impact of rotavirus disease on child health, and the economic burden on families and the healthcare system. A remaining challenge is the lower vaccine protective efficacy observed in children in low- and middle-income countries (LMICs) where the mortality and hospitalizations due to severe rotavirus disease still occur [1]. The role of nutrition in influencing the immune response to a rotavirus vaccine is the focus of the accompanying paper by Isanaka and colleagues published in this issue of PLOS Medicine [2].Understanding why over 87% of children vaccinated with a rotavirus vaccine in low child mortality countries are protected against severe rotavirus disease compared to approximately 44% (27% to 59%) of children in high child mortality countries is not well understood [3]. As an orally administered vaccine, initial focus has been on factors that could neutralize the live vaccine virus within the gut lumen. Most rotavirus vaccines are administered in a buffered formulation to reduce the risk of neutralization of the vaccine virus by gastric acid [4]. In early clinical trials, fasting prior to vaccination was applied in an effort to reduce the potential impact of breast milk antibodies. This is now not considered necessary [5]. A difference in the gut microbiome in infants from high-income and LMICs has been observed, although the administration of a probiotic did not result in improved rotavirus vaccine immunogenicity [6,7]. Rotaviruses use histo-blood group antigens present on the gut epithelial surface in the initial phase of virus attachment and cellular entry [8]. It has been proposed that population variability in histo-blood group antigen phenotype, specifically Lewis and secretor status, may explain the genotype diversity of rotavirus between regions and the responses observed to live oral rotavirus vaccines that may be VP4 [P] genotype dependent [8].Childhood malnutrition is associated with reduced immune responses to a range of infections, and in the immune response to vaccines, including rotavirus vaccines [9]. Macro and/or micronutrient deficiencies have been linked to a range of abnormalities in T and B cell function, mucosal immunity, cytokine production, and responses [9]. However, there are limited data on the impact of maternal nutritional supplements on the immune responses following vaccination of their infants. Isanaka and colleagues’ cluster-randomized study was nested within a double-blind, placebo control vaccine efficacy trial. It evaluated the effect of 3 different maternal nutritional supplements on serum antirotavirus immunoglobulin A (IgA) seroconversion following administration of 3 doses of the oral rotavirus vaccine Rotasiil (G1, G2, G3, G4, G9) in infants in Niger [2]. The daily supplements were commenced prior to 30 week’s gestation in a population of women at risk of macro- and micro-nutrient malnutrition, although maternal anthropometry and micronutrient status before and after supplementation is not reported. The supplement options included the “standard of care” iron−folic acid (IFA) supplement, a multi-micronutrient (MMN) supplement at levels at or double the US recommended dietary allowance for pregnant women, or the same MMN supplement with an additional energy and protein component. As all groups received a supplement, this study was designed to provide a comparison between supplement groups rather than a comparison with no supplement. Across all supplement groups, the serum antirotavirus IgA seroconversion following administration of 3 doses of Rotasiil was modest at 39.6% and only 10% greater than that observed in the placebo group (29.0%). The rate of seroconversion did not differ between supplement groups, although serum IgA geometric mean titres were not reported. In similar study in The Gambia, an enhanced antibody response to the diphtheria-tetanus-pertussis (DPT) vaccine was observed in the infants of mothers who had received a prenatal MMN and protein−energy supplement, when compared to those who received the “standard of care” iron−folate supplement [10]. Of note, the supplement used in The Gambia study contained more energy and protein when compared to the MMN plus energy and protein used in this study in Niger (The Gambia study versus Niger study; energy [kcal]: 746 versus 237; protein [grams]: 20.8 versus 5.2; lipids [grams]: 52.6 versus 20). Whether the differences reported in vaccine immune responses between these 2 studies reflect these differences in the composition of the supplement, differences specific to the vaccine (DPT versus rotavirus vaccine), study sample size or characteristics of the study population requires further study.Rotavirus vaccines save lives and prevent hospitalizations due to rotavirus disease in children. Efforts to improve the level of protection provided by rotavirus vaccines, particularly in LMICs, have the potential to maximize the impact on these vaccines on global child health. Improving the nutritional status of infants through the provision of macro- and micro-nutrient supplements to pregnant mothers in high-risk populations may optimize immune responses to rotavirus vaccines; however, the specific composition of the prenatal supplement requires further investigation.     

Cesarean section: More than a maternal health issue

A cesarean section (CS) can be a lifesaving intervention when medically indicated, but it may also lead to adverse short- and long-term health effects for women and children.

Marleen Temmerman and Abdu Mohiddin discuss the accompanying study by Enny Paixao and colleagues on associations between cesarean section birth and child mortality up to age 5.

Therefore, the accompanying research study by Paixao and colleagues published in PLOS Medicine, looking at CS and associated child mortality in Brazil, provides further valuable evidence on the balance of benefits and risks [1].CS rates are rising worldwide: Boerma and colleagues, on the basis of data from 169 countries including 98.4% of the world’s births, estimated that 29.7 million (21.1%) births occurred by CS in 2015, almost double the number of CS births in 2000 (16.0 million, 12.1%) [2]. In a further study investigating CS rates in specific obstetric populations using the Robson system, which classifies all deliveries into one of 10 groups on the basis of 5 parameters: obstetric history, onset of labour, foetal lie, number of neonates, and gestational age, there was an increase of CS across most Robson groups, especially after induction of labour in multiparous women [3].WHO guidance is clear that CS is essential for those who need it, specifying a recommended rate of 10% to 15% to improve maternal and perinatal outcomes and prevent maternal and neonatal mortality and morbidity [4]. Yet, given the increasing use of CS, particularly without medical indication, a more complete understanding of its health effects on women and children has become crucial. The maternal sequelae of CS are well described, while long-term consequences for child health require more research. There is emerging evidence that babies born by CS have different hormonal, physical, bacterial, and medical exposures and that these exposures can subtly alter neonatal physiology. Short-term risks (within 3 years) of CS can include altered immune development; an increased likelihood of allergy, atopy, and asthma; and reduced intestinal gut microbiome diversity [5]. In a systematic review, CS was found to be a risk factor for respiratory tract infections (pooled odds ratio (OR) = 1.30 for asthma) as well as for obesity (pooled OR = 1.35) in children [6]. In a further study including 327,272 neonates born by vaginal delivery and 55,246 by elective CS investigating neonatal respiratory morbidity in relation to mode of delivery, there was a 95% higher risk in neonates delivered by elective CS than in neonates born by spontaneous vaginal delivery [7]. Further, Alterman and colleagues described a moderately elevated risk of severe lower respiratory tract infections during infancy in infants born by planned CS, as compared to those born vaginally [8]. Infants born by planned or emergency CS may also be at a small increased risk of severe upper respiratory tract infections, with a stronger estimated effect if including the indirect effect arising from planning the cesarean birth for an earlier point in gestation than would have occurred spontaneously [8].However, the extent to which CS, in particular nonmedically indicated CS, benefits or reduces child survival remains unclear. Therefore, Paixao and colleagues conducted a population-based cohort study in Brazil by linking routine data on live births from 2012 to 2018 and assessing mortality up to 5 years of age [1]. Women with a live birth were classified into a Robson group based on pregnancy and delivery characteristics. The analysis of 17,838,115 live births showed that live births to women with low expected frequencies of CS (Robson groups 1 to 4) had a higher death rate up to age 5 years compared with vaginal deliveries (HR = 1.25, 95% CI: 1.22 to 1.28; p < 0.001). This means that CS was associated with a 25% increase in child mortality in infants born via CS in Robson groups with low expected frequencies of CS (i.e., low-risk mothers). In groups with high expected frequencies of CS (i.e., high-risk mothers), mortality rates were lower among infants born via CS, supporting the benefits of clinically indicated CS.This large study shows how important it is to optimise the use of CS, which is increasingly overused leading to global concern. Underuse of CS leads to maternal and perinatal mortality and morbidity, and yet, conversely, overuse of CS has not shown benefits and can create harm. As the frequency of CS continues to increase, interventions to reduce unnecessary CS are urgently needed. As described by Betrán and colleagues, many factors can affect rates of CS, and these may be associated with women, families, health professionals, and healthcare organisations and systems, being influenced by behavioural, psychosocial, health system, and financial factors [9]. These authors concluded that interventions to reduce overuse of CS must be multicomponent and locally tailored, addressing women’s and health professionals’ concerns, as well as reflecting health system and financial factors [9].Paixao and colleagues’ study provides evidence that either overuse or underuse of CS is associated with child survival, and the findings will help pregnant women and their providers to make informed decisions as to whether CS is appropriate for them. The authors should be commended for carrying out this big data record linkage study, which paves the way for further analyses to study risk profiles using other available population-level data. At a health policy level, the paper shows the significant challenge to child population health that the sequelae of low-risk CS pose, especially in countries with high CS rates such as Brazil at 56% [10]. This represents an avoidable threat to some of the gains to child mortality and morbidity seen over the past few decades and to the achievement of the UN’s Sustainable Development Goal 3 to ensure health and well-being at all ages [11]. Policymakers and civil society groups should take note and act by implementing the recommendations of the 2018 International Federation of Gynaecology and Obstetrics (FIGO) position paper, calling for “joint actions with health professionals, governmental bodies, women’s groups and the healthcare insurance industry to stop unnecessary caesarean sections” [12].     

Extending precision medicine tools to populations at high risk of type 2 diabetes

In this Perspective, Shivani Misra and Jose C Florez discuss the application of precision medicine tools in under-represented populations.

People of South Asian ancestry carry a 3-fold higher risk of developing type 2 diabetes (T2D) than white European individuals [1], with the disease typically manifesting a decade earlier [2] and at a leaner body mass index (BMI) [3]. The South Asian population is often considered as a uniform group, but significant heterogeneity in the prevalence of T2D and its phenotype manifestations across south Asia exists, with a higher prevalence in those from Bangladeshi and Pakistani communities [4]. Genome-wide association studies (GWAS) have not fully explained the excess risk observed in South Asian individuals [5,6], and attention has turned to strategies through which genetic information may be leveraged for clinical benefit, such as generating an aggregate of weighted single nucleotide polymorphisms (SNPs) that capture the overall genetic burden for a trait into a polygenic score (PS) (sometimes described as a polygenic risk score) [7]. However, constructing a PS remains challenging in populations that are underrepresented in GWAS.In the accompanying article in PLOS Medicine [8], Hodgson and colleagues investigate the use of a PS to predict T2D in the Genes & Health (G&H) cohort, addressing a key knowledge gap in the applicability of such tools in underrepresented ethnicities. G&H is a pioneering community-based cohort of approximately 48,000 participants of predominantly British Bangladeshi and Pakistani heritage combining genetic and longitudinal electronic healthcare record data. They first assessed the transferability of known T2D genetic risk loci in G&H and constructed a PS using variants from a multi-ancestry GWAS, adjusting the scores for Pakistani and Bangladeshi individuals and selecting the one with the highest odds for prediction. This score was then integrated with 3 versions of a clinical model (QDiabetes) to predict T2D onset over 10 years in 13,642 individuals diabetes free at baseline. The authors show that incorporation of a PS with QDiabetes provided better discrimination of progression to T2D, especially in those developing T2D under 40 years of age and in women with a history of gestational diabetes. Finally, they incorporated the PS into cluster analyses of baseline routine clinical characteristics, replicating clusters defined in European populations and identifying a cluster resembling a subgroup of severe insulin deficiency. This study significantly advances the field on the transferability of PSs, reproducibility of T2D clusters, and clinical translation of these findings to precision medicine for diabetes.     

Evaluation of portable devices for medicine quality screening: Lessons learnt,recommendations for implementation,and future priorities

Céline Caillet and co-authors discuss a Collection on use of portable devices for the evaluation of medicine quality and legitimacy.

Summary points

• Portable devices able to detect substandard and falsified medicines are vital innovations for enhancing the inspection of medicines in pharmaceutical supply chains and for timely action before they reach patients. Such devices exist, but there has been little to no independent scientific evidence of their accuracy and cost-effectiveness to guide regulatory authorities in choosing appropriate devices for their settings.
• We tested 12 portable devices, evaluated their diagnostic performances and the resources required to use each device in a laboratory.
• We then assessed the utility and usability of the devices in medicine inspectors’ hands in a pharmacy mimicking a real-life Lao pharmacy.
• We then assessed the health and economic benefits of using portable devices compared to not using them in a low- to middle-income setting.
• Here, we discuss the conclusions and practical implications of the multiphase study discussed in this Collection. We discuss the results, highlight the evidence gaps, and provide recommendations on the key aspects to consider in the implementation of portable devices and their main advantages and limitations.

Global concerns over the quality of medicines, especially in low- and middle-income countries (LMICs) are exacerbated by the Coronavirus Disease 2019 (COVID-19) pandemic [1,2]. The World Health Organisation (WHO) estimated that 10.5% of medicines in LMICs may be substandard or falsified (SF) [3]. “Prevention, detection, and response” to SF medical products are strategic priorities of WHO to contribute to effective and efficient regulatory systems [4]. Numerous portable medicine screening devices are available on the market, holding great hope for detection of SF medicines in an efficient and timely manner, and, therefore, might serve as key detection tools to inform prevention and response [5,6]. Screening devices have the potential to rapidly identify suspected SF medical products, giving more objective selection for reference assays, reducing the financial and technical burden. However, little is known regarding how well the existing devices fulfil their functions and how they could be deployed within risk-based postmarketing surveillance (rb-PMS) systems [5–7].We conducted, during 2016 to 2018, a collaborative multiphase exploratory study aimed at comparing portable screening devices. This paper accompanies 4 papers in this PLOS Collection “A multiphase evaluation of portable screening devices to assess medicines quality for national Medicines Regulatory Authorities.” The first article introduced the multiphase study [8]. In brief, 12 devices (S1 Table) were first evaluated in a laboratory setting [9], to select the most field-suitable devices for further evaluation of their utility/usability by Lao medicines inspectors [10]. Cost-effectiveness analysis of their implementation for rb-PMS in Laos was also conducted [11]. The results of these 3 phases were discussed in a multistakeholder meeting in 2018 in Vientiane, Lao PDR (S1 Text). The advantages/disadvantages, cost-effectiveness, and optimal use of screening devices in medicine supply chains were discussed to develop policy recommendations for medicines regulatory authorities (MRAs) and other institutions who wish to implement screening technologies. A summary of the main results of the multiphase study is presented in S2 Table.As far as we are aware, this is the first independent investigation comparing the accuracy and practical use from a public health perspective, of a diverse set of portable medicine quality screening devices. The specific objective(s) for which the portable screening technologies are implemented, their advantages/limitations, costs and logistics, and the development of detailed standard operating procedures and training programmes are key points to be carefully addressed when considering selection and deployment of screening technologies within specific rb-PMS systems (Fig 1).Open in a separate windowFig 1Major proposed considerations for the selection and implementation of medicine quality screening device.Each circle represents a key consideration when purchasing a screening device, grouped by themes (represented by heptagons). When the shapes overlap, the considerations are connected. For example, standard operating procedures are needed for the implementation of devices and should include measures for user safety. The circle diameters are illustrative.Here, we utilise this research and related literature to discuss the evidence, gaps, and recommendations, complementary to those recently published by the US Pharmacopeial Convention [12]. These discussions can inform policy makers, non-governmental organisations, wholesalers/distributors, and hospital pharmacies considering the implementation of such screening devices. We discuss unanswered research questions that require attention to ensure that the promise these devices hold is realised.     

Building global health research capacity to address research imperatives following the COVID-19 pandemic

Peter Kilmarx and Roger Glass discuss strengthening health research capabilities as a response to the COVID-19 pandemic.

Research and development of new tools and interventions are necessary to improve global health, as has been made apparent by the Coronavirus Disease 2019 (COVID-19) pandemic [1]. As of mid-July 2021, there have been nearly 190 million cases reported worldwide and more than 4 million deaths; and yet, less than a year after the outbreak was first reported, in an unprecedented global effort, researchers had developed home rapid self-tests [2], established treatment protocols proven effective to improve survival [3], and discovered highly effective vaccines that are already being produced and administered at a large scale [4].The COVID-19 pandemic also illustrates the importance of having research capacity in place as a critical element of pandemic preparedness. China, with its robust research capacity, was able to rapidly sequence the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus in January 2020 [5] and quickly share the results, thereby jumpstarting global development of diagnostic tests and vaccines. In contrast, when outbreaks have occurred in countries with less research capacity, the development of countermeasures—diagnostics, therapeutics, and vaccines—may be delayed. We examined the relationship between a country’s preexisting research capacity and the output of scientific publications in PubMed by the country’s scientists following an outbreak. In the first 2 years after the Ebola outbreak was recognized in Guinea, only 42 papers on Ebola were published with authors with a Guinean affiliation, and there were significant challenges in launching Ebola treatment and vaccine studies. From Brazil, with its strong research infrastructure, 312 publications about Zika were authored by scientists with a Brazilian affiliation in the 2 years after that outbreak was detected, and substantial progress was made in rapidly characterizing the newly recognized, diverse clinical manifestations. Finally, authors affiliated with a Chinese institution published 8,921 articles on COVID-19 since the current outbreak was recognized, with remarkable progress in developing medical countermeasures.Anticipating significant progress in controlling COVID-19 in 2021, what are the future priorities for global health research? A helpful guide is the 2019 report of the Global Burden of Diseases, Injuries, and Risk Factors Study [6]. This comprehensive synthesis showed that the largest absolute increases in number of disability-adjusted life years between 1990 and 2019 mostly included noncommunicable diseases, i.e., ischemic heart disease, diabetes, stroke, chronic kidney disease, and lung cancer. These illnesses have overlapping risk factors—hypertension, high fasting plasma glucose, high body mass index, tobacco use, and ambient air pollution—which are also highly prevalent and mostly increasing over time [7], further suggesting important areas for research. Notably, some of these diseases and risk factors are also predisposing factors for more severe COVID-19 and prolonged symptoms post-COVID-19.Many other critical COVID-19 research questions in the NIH-Wide Strategic Plan for COVID-19 Research [8] remain unanswered, and new urgent questions have arisen. These include the following: What can we learn from how genetic and other factors explain the high individual variation in the clinical course of COVID-19 to improve treatment interventions? How can diagnostic tests be optimized for home use and low-resource settings, and can testing platforms be created for rapid adaptation with new emerging pathogens? With the potential for waning immunity and immune escape variants, what strategies will be needed for COVID-19 vaccine booster doses? Lastly, how best can public health interventions and medical countermeasures be delivered to reduce poor outcomes, especially in racial/ethnic minority and other vulnerable populations?Several other important perspectives on threats to global health cut across multiple disease entities and provide useful frameworks and new imperatives for prioritizing global health research. The One Health concept encompasses interconnections between humans, animals, plants, and the environment and embraces a transdisciplinary approach to address major emerging threats including zoonotic diseases (e.g., COVID-19), vector-borne diseases, antimicrobial resistance, food safety, and environmental contamination [9]. Another framework is Planetary Health, which focuses on the already large and growing health impacts of our extensive disruptions of earth’s systems, especially climate change, but also declining biodiversity, increasing pollution, and shortages of fresh water, land, and ocean resources [10]. In addition, humanitarian crises such as armed conflicts, natural disasters, and disease outbreaks are impacting more people than ever before. New research approaches and partnerships are needed to address evidence gaps and to establish capacities for future challenges [11]. The impact of COVID-19 on routine health services is a striking current example. Lastly, implementation research on promoting the uptake of evidence-based interventions and policies into routine healthcare and public health settings is needed across each of these fields of health research to address persistent gaps between the promise of proven effective innovations and their successful implementation, especially in underserved and marginalized populations that have been more severely impacted by COVID-19 [12].We believe the greatest priority should be on building health research capacity in low- and middle-income countries (LMICs) where the health burdens and threats are greater and research capacity is often lower than in higher-income countries. Basic pillars of capacity are needed to establish a robust, responsive research environment. Foremost among these is human capacity. Over decades of experience, we have learned that developing research leaders in LMICs requires well-trained individuals with protected time to conduct research and with strong mentorship and networking with both international and local scientists. It is encouraging to see such investigators trained in other research topics such as HIV and tuberculosis now emerge as leaders in their country’s response to the COVID-19 pandemic in Asia, Africa, and the Americas [13]. Other critical capacities include laboratory testing, data management and statistical analysis, clinical trial and community research site development, behavioral and social science, community engagement, ethical review boards, and regulatory systems. A promising emerging approach is to use basic metrics of national and institutional health research capacity to help coordinate and increase efficiency of capacity building efforts, identify and support countries with lowest capacity levels, and facilitate increased research on national health priorities [14]. As we have seen with COVID-19, these capacities can also be rapidly brought to bear to address new health threats. Notably, of the 30 countries taking part in the SOLIDARITY trial of COVID-19 treatment, 16 are LMICs [15]. A critical limitation and emerging priority underscored by COVID-19 is in vaccine research, development, and manufacturing capacity, especially in Africa [16].COVID-19 has necessitated many other substantial changes in our usual practices of global health research, some of which are likely to persist. Use of digital platforms for telecommunications has exploded. In many settings, telework and distance learning are proving to be very effective and sometimes preferable to the expense and risk of face-to-face meetings. We have seen greater participation in many webinars and network meetings, especially from early-career and LMIC colleagues who did not have the time or the budget for in-person meetings [17]. Importantly, the environmental costs of these virtual meetings are also much lower. Along with increases in telemedicine, there have also been advances in teleresearch whereby participants can be enrolled or followed via their mobile phones, potentially decreasing the costs and barriers to participation and improving study retention. The speed of research, formation of collaborations, and communication of results have all increased remarkably with digital collaboration platforms and rapid publication, including publication of preprints, which are now available on PubMed [18]. International collaboration and coordination in research and regulatory processes have also been critical to the rapid development of medical countermeasures through platforms such as the Access to COVID-19 Tools (ACT) Accelerator of the World Health Organization [19] and the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership led by the National Institutes of Health [20].Unfortunately, there has also been an “infodemic” of misinformation (i.e., any false information) and disinformation (deliberately false or misleading information) around the source and impact of COVID-19 and the science of its prevention and treatment [21]. This is not a new phenomenon, but with the growth of digital platforms with domestic and international rivalries, a major threat has emerged requiring research to better understand and counter that threat.Finally, COVID-19 is likely to recalibrate perspectives of levels of expertise in north–south relationships among higher- and lower-income countries. At the time of this writing, the public health, healthcare system, and policy approaches in the COVID-19 response of many high-income countries in the north have greatly underperformed in comparison to some lower-income countries in the global south, especially in regard to protecting vulnerable and marginalized populations. This has increased momentum to democratize global health, with the recognition that a new sense of humility and equity will be critical to understand all of the lessons to be learned and improve global health following COVID-19. We applaud the growing role of LMIC scientists in setting the global health research agenda [22].In conclusion, while the COVID-19 pandemic has already taken a devastating global toll on global health and well-being, it has also provided a strong example of the importance of health research capacity as an essential element of pandemic preparedness. The world faces a wide range of health challenges, from chronic diseases and risk factors to emerging global threats. Building research capacity, especially in countries with lower levels, while learning the lessons of COVID-19, must become a higher priority to achieve our current shared global health goals while increasing resilience to address future health threats.     

Why restricting access to abortion damages women’s health

Dr. Caitlin Moyer discusses the implications, for women globally, of restricting access to abortion care.

In late June, the landmark Roe v. Wade ruling was overturned by the United States Supreme Court, a decision, decried by human rights experts at the United Nations [1], that leaves many women and girls without the right to obtain abortion care that was established nearly 50 years ago. The consequences of limited or nonextant access to safe abortion services in the US remain to be seen; however, information gleaned from abortion-related policies worldwide provides insight into the likely health effects of this abrupt reversal in abortion policy. The US Supreme Court’s decision should serve to amplify the global call for strategies to mitigate the inevitable repercussions for women’s health.Upholding reproductive rights is crucial for the health of women and girls worldwide, and access to a safe abortion is central to this, yet policies in several countries either severely limit or actively prevent access to appropriate abortion care and services [2]. However, there is little to suggest that those countries and jurisdictions with abortion bans or heavily restrictive laws see fewer abortions performed. According to a modeling study of pregnancy intentions and abortion from the 1990s to 2019, rates of unintended pregnancies ending in abortion are broadly similar regardless of a country’s legal status of abortion, and unintended pregnancy rates are higher among countries with abortion restrictions [3]. Abortion is widely considered to be a low-risk procedure. Abortion-related deaths most likely occur in the context of unsafe abortion practices and are reported to account for 8% (95% UI 4.7–13.2%) of maternal deaths [4], making them a top direct contributor to maternal deaths globally, alongside hemorrhage, hypertension, and sepsis. Restrictive abortion policies may not lower the overall rates of abortion, but they can drive increasing rates of unsafe abortions, as women resort to seeking abortions covertly. Such abortions are often performed by untrained practitioners or involve harmful methods. Perhaps unsurprisingly, most abortions that take place in countries with restrictive abortion access policies are not considered safe [5], potentially contributing to maternal morbidity and mortality. A study of 162 countries found that maternal mortality rates are lower in countries with more flexible abortion access laws [6], suggesting that changes in abortion policies could have grievous implications for maternal deaths.It is not yet known if the reneging of federal protection of abortion rights will impact maternal deaths in the US; however, in the years following the 1973 Roe v. Wade decision, numbers of reported deaths associated with illegal abortions, defined as those performed by an unlicensed practitioner, declined, hovering between zero and 2 deaths from the 1980s to 2018, down from 35 in 1972 [7] and 19 reported in 1973 [8]. It is possible that limits on access to timely and safe abortion care could drive this number back up and add to the already unacceptably high maternal mortality rate in the US, potentially exacerbating the persistent disparities in maternal mortality based on socioeconomic deprivation, race and ethnicity, and other factors [9].Legal and social barriers that impede access to safe abortions are detrimental to the health and survival of women and girls; thus, constructing policies ensuring access to safe abortion services should be an urgent priority. Placing undue hurdles between women and access to abortion care is associated with undesirable health outcomes. For example, a 2011 change to medication abortion laws in one US state that involved increased medication costs and restricted the timing and location where abortion services could be provided was associated with an increase in rates of women requiring additional medical interventions [10]. Lending international weight to this argument, dissolution of barriers to safe abortion access was emphasized in the March 2022 update of WHO guidance on abortion care [11], echoing a 2018 comment on the International Covenant on Civil and Political Rights released by the United Nations Human Rights Committee [12] that called on member states to remove existing barriers and not enact new restrictions on provision of safe abortion services so that pregnant women and girls do not need to turn to unsafe abortions.In jurisdictions where prohibitive policies exist, more could be done to counter the impacts of new barriers by changing how abortion care is delivered and increasing accessibility. Protocols for the safe self-management of abortion can be implemented alongside provision of information and provider support. WHO guidance [11] suggests expanding the breadth of practitioners authorized to prescribe medical abortions to include nurses, midwives, and other cadres of healthcare workers. The guidelines also mention telemedicine as an approach to circumvent obstacles to seeking safe abortion services [11]. For those with access to the necessary technology, telemedicine services together with self-management of medication abortion can overcome travel-related barriers and ensure the privacy of those seeking treatment. Demands for telehealth services increased during the COVID-19 pandemic, and, according to one study, remote provision of abortion services in the US may be a promising option to counteract barriers and facilitate access [13].In 2022, restrictive policies or outright bans on abortion services are discriminatory against women, obstructing their right to maintain autonomy over their own sexual and reproductive health. A post-Roe legal landscape that renders abortion more difficult or impossible to obtain safely will exacerbate an increasingly bleak picture of maternal health in the US; however, the US is just one example where increased effort is needed to overcome barriers to improving women’s healthcare. The reality is that such barriers continue to represent a threat to the health of women worldwide. Evidence-based changes to policy and practice that break down barriers and build new roads are required to enable women to access the healthcare they need.     

Closing the health equity gap: A role for implementation science?

Beryne Odeny discusses strategies to improve equity in health care and health research.

WHO defines health equity as “the absence of unfair and avoidable or remediable differences in health among population groups defined socially, economically, demographically, or geographically or by other means of stratification” [1]. Yet, contrary to this fundamental aspiration and the international mandate on universal health coverage (UHC), almost 50% of the world’s population does not receive needed health services, and progress toward health equity remains elusive [2].     

Social justice now for an equitable tomorrow: Reflections from the Consortium of Universities for Global Health Conference 2022

PLOS Medicine editors Beryne Odeny and Callam Davidson report from the Consortium of Universities for Global Health conference.

“Healthy People, Healthy Planet & Social Justice,” was the theme of the second virtual Consortium of Universities for Global Health (CUGH) 2022 conference, held from March 28 to April 1, 2022. In the face of escalating global health and security challenges, this bold theme and the associated agenda (https://cugh.confex.com/cugh/2022/meetingapp.cgi) were welcomed with great anticipation by thousands of stakeholders from 135 countries across the globe. As adeptly put by Dr. Peter A Singer, Special Advisor to the Director General of WHO, the fundamental question at the heart of social justice is simple: “Do we value every human life equally?”. In answering this question, we must acknowledge that what we now consider to be the discipline of global health is in fact anchored by deep and tortuous colonialist roots that continue to bear the fruits of injustice to this day. Over the course of the conference, speakers conceptualized a human rights framework for rethinking global health. This perspective piece presents a curated synopsis of the main CUGH conference and preceding satellite sessions.The conference commenced with a call from Thuli N. Madonsela, Former Public Protector of South Africa, to uphold the sacrosanct respect for human life given the interconnectedness of humanity’s existence on our shared planet. Her insights on social justice as interpreted within the framework of Ubuntu philosophy brought a breath of fresh air to the debate on neo-colonialism. Thuli’s keynote concluded with an optimistic outlook: “Investing in justice today is like throwing a javelin into the future, one that will become the guardrail for sustainable development.”Globalization has brought tremendous advances in industry, commerce and trade, and eye-watering financial gains for some in both high income countries (HICs) and low- and middle-income countries (LMICs). Alongside these gains, global openness has contributed to the swift spread of the most formidable maladies of the present day, not least of which are the dual epidemics of COVID-19 and non-communicable diseases (NCDs), climate change and global warming, global corruption, conflict and wars, and ensuing humanitarian crises [1,2]. Pervasive health inequities which compound the toll of these calamities are a stark reminder of how global health has failed the most vulnerable. The COVID-19 pandemic continues to be the litmus test against which our truest values are tested. “If we can’t handle COVID-19, what does it mean about our approach to tackling climate change?”–this was a germane question from a speaker reflecting on inequitable vaccine distribution [3,4].Comparable to other health sectors awash with global funding, the global COVID-19 vaccine delivery effort has created fertile ground for corruption, due to a toxic combination of high commodity demand, unprecedented resource allocation, and perennially weak health systems with fragmented supply chains [5,6]. It has been shown that corruption can fuel vaccine hesitancy by creating suspicion and mistrust in science and government. This has been witnessed in some countries in Asia, despite commendable levels of vaccine coverage. In contrast, the long-standing National Immunization Program in Brazil created a culture of vaccination and helped minimize hesitancy (despite the influence of the country’s present leadership) [7]. Other factors beyond vaccine-specific factors include contextual, individual, and group influences that can inform hesitancy; these additional factors can be exploited to undergird vaccine efforts–barbers delivering vaccines, and outreach efforts by Buddhist monks, for example.Beyond the COVID-19 pandemic is the rise of Commercial Determinants of Health (CDoH). CDoH refer to approaches used by corporate sectors to promote products that are detrimental to health [8]. These products include processed foods and drinks, alcohol, and tobacco–factors that are fueling the rising burden of NCDs–more so in LMICs and among the socially disadvantaged in HICs, who bear the largest brunt of related mortality [9]. Unrestrained access to and use of harmful products such as heavy metals and asbestos, pose a threat to poor and vulnerable communities in proximity to mines and industries. These injustices are propagated by powerful corporates that stealthily evade restrictive public health policies to protect their profit margins [10]. A downstream impact of the surge of NCDs in LMICs, is the intense suffering among those dying from terminal illnesses due to the unethical lack of access to palliative care. There is a dearth of palliative resources, including trained health providers, particularly in low resource contexts such as fragile and conflict settings, and among ethnically diverse groups in HICs [11].The COVID-19 and NCDs conundrums are accompanied by another global health woe–namely the paternalist nature of HIC support for LMICs. Paternalistic support presents in the form of tied aid and technical support which have been used to determine the seat of power, with regard to who holds the money, who generates knowledge, who practices, who publishes, and, ultimately, who thrives in the global health ecosystem. This is demonstrated by institutionalized power asymmetries across funding, academic research, and global health priority setting, which disproportionately favor researchers from HICs at the expense of those from LMICs. To date, less priority has been accorded to health issues of concern, beyond infectious diseases, in the poorest parts of the world such as cancer among other NCDs. Conditionality and increased vertical funding have been shown to limit LMICs’ autonomy to finance their primary health challenges and are linked to reduced government health expenditure with commensurate increases in out-of-pocket/ household expenditure. The health sector is known to be highly corrupt as well as it is well-resourced (accounting of 10% of overall GDP spending) [12]. The lethal mixture of politics, power, and corruption in LMICs is a brewing pot for injustice as it perpetuates a vicious cycle of poverty and disease among the most vulnerable.Tackling corruption at international and national levels requires multisectoral attention to wider issues of global security, giving people a voice and providing the backing of legal frameworks, to demand accountability and transparency without fear of retaliation. Empowering global health stakeholders and civil societies to engage corporate and political sectors in planetary and global health discourse is an essential tool for fostering health equity, environmental justice, and social justice in business paradigms [2,8]. In this way, leaders can be enlightened and held accountable for performance of equity-based indicators e.g., proportion of specific global goods going to LMICs. Within the global health fraternity, decolonizing global health through inclusive partnerships is necessary to remove longstanding hierarchies in decisional spaces, and shift the balance of power so that more indigenous community actors can define their problems and find relevant solutions [13]. Inspirational stories of the national COVID-19 taskforce in Uganda demonstrate how active communities can promote vaccine uptake [14]. Scaling up community-led integrated health care efforts can extend beyond the pandemic and may even accelerate realization of the UN Sustainable Development Goals. Sustainable funding streams, training, and capacity development to create a robust workforce and enabling environments to host research in LMICs should be at the center of the global health agenda. Other considerations would include leveraging integrated digital and information systems that foster inclusion of marginalized populations in program planning and service delivery, and in so doing uphold equity and inclusion in health system strengthening globally.Decolonizing global health and upholding social justice will be crucial to containing the impending NCD tsunami, pandemics beyond COVID-19, and climate change. However, throwing off the pernicious colonial legacy presents one of the biggest challenges in global health. No one is exempt from the experience of neo-colonialism regardless of location; thus, all hands are needed on deck to disrupt and resist its existence. Dr. Madhukar Pai of McGill University in Montreal, Canada, and colleagues emphasized that allyship is invaluable to this end–it seeks to identify what the most privileged can do to elevate the voices of those suffocating under the weight of injustice [15]. Beyond speaking up against inequities, meaningful allyship needs disruptive change, sometimes as far as ceding positions of power. The global health community is at a crossroads, a defining moment since its existence, and needs to decide which way to proceed–whether to remain passive to entrenched notions of polarization or to embrace a disruptive paradigm shift that defends social justice and secures sustainable development for all. The question remains–are we ready to shift?     

Assisted reproduction technology and long-term cardiometabolic health in the offspring

Ronald Ma and co-authors discuss Emma Norrman and colleagues’ accompanying research study on the health of children born with assisted reproductive technology.

Since the birth of the first baby with the aid of in vitro fertilization (IVF) in July 1978, more than 9 million children have since been born through IVF or other assisted reproduction technology (ART). From a report covering around 2/3 of world ART activity, it was estimated that more than 4.4 million ART cycles have been initiated between 2008 and 2010, which resulted in 1.14 million births during that period [1]. From 1997 to 2016, the numbers of recorded ART treatment have increased by 5.3-fold in Europe, 4.6-fold in the United States of America, and 3.0-fold in Australia and New Zealand [1]. In an accompanying study in PLOS Medicine, Emma Norrman and colleagues address the health of babies born after ART [2].While initially met with considerable skepticism and controversy, the large number of healthy babies born over the last 4 decades is testament to the success and safety of IVF, which has transformed the lives of many couples and families. Nevertheless, given the appreciation of the Developmental Origins of Health and Disease (DOHaD) hypothesis, which posits that insults during critical times of development (including in utero or early life) may modify an individual’s phenotype and alter later risk of disease in adulthood, as well as previous demonstration of potential epigenetic changes following ART, there has been rekindled interest in the potential long-term effects of ART on offspring health [3]. In a large retrospective Nordic population-based cohort study of all children born after ART between 1982 and 2007, there was no significant increase in overall cancer rates among children born after ART, compared to children born after spontaneous conception (SC) [4]. Questions have also been raised about the long-term cardiovascular health of offspring born after ART, as several mechanisms have been postulated to potentially contribute to impaired cardiovascular health, including suboptimal culture conditions, ART-induced epigenetic changes, as well as indirect effects through low birthweight, thereby contributing to altered cardiovascular phenotype [5] (Fig 1). A systematic review and meta-analysis did not show evidence of increased cardiovascular risk or diabetes for women following ART, though there was comparatively less data to address offspring risk [6]. In line with a recent systematic review and meta-analysis [7], previous small studies have found increased adiposity, cardiometabolic risk, and blood pressure among offspring born after ART, potentially due to altered gene expression [8,9]. However, issues regarding potential selection bias have been raised for the small studies included.Open in a separate windowFig 1A DOHaD perspective on the potential relationship between ART and later risk of T2D and CVD.The putative link is highlighted by the dotted outline. ART, assisted reproduction technology; CVD, cardiovascular disease; DOHaD, Developmental Origins of Health and Disease; EDCs, endocrine-disrupting chemicals; GDM, gestational diabetes; ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilization; ncRNA, noncoding RNA; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes. (adapted with permission from Ma and colleagues [13]).Norrman and colleagues conducted a large population-based study from the Committee of Nordic ART and Safety (CoNARTaS) cohort, which included all individuals born in Norway, Sweden, Finland, and Denmark between 1984 and 2015, including 122,429 children born after ART, and more than 7.5 million children born after SC, to investigate the risk of cardiovascular disease (CVD), diabetes, and obesity following ART compared to SC. Offspring were followed for a mean 8.6 years in children born after ART and 14.0 years for children born following SC. Although the crude rates for CVD and type 2 diabetes (T2D) were higher among children born after ART, there were no significant difference in rates after adjustment for measured confounders. The study noted a significant increase in the risk of obesity among children born to ART, though the risk was modest, with adjusted HR 1.14 (CI 1.06 to 1.23, p = 0.001). The design of the study also meant that it could not address whether any increased risk in the offspring might be related to maternal causes of infertility (such as polycystic ovary syndrome), rather than the ART. In contrast to the previous systematic review that suggested significant increase in cardiometabolic risk factors in ART offspring, the authors concluded that the cardiometabolic outcomes in ART children are, in general, reassuring. However, further studies with longer follow-up are needed.The study provided much-needed medium-term outcome data addressing this important question of long-term cardiometabolic risk in children born after ART. By combining high-quality Nordic registers, Norrman and colleagues have been able to create a uniquely large cohort of ART children in order to compare their risk of cardiovascular health with children born after SC. Such population-based design provided high coverage rate and high validity, such that missing data and the risk of selection bias can be minimized. However, there were some notable limitations of the study, including the relatively short follow-up period, especially among children born to ART. The number of clinical outcomes of interest was limited, hence restricting statistical power to detect differences in outcome. Although the use of national registries has minimized any risk of selection bias, the definitions of outcomes were based on inpatient and outpatient attendance and may be associated with some ascertainment bias, especially in relation to capturing obesity outcomes. There is also a significant proportion with missing maternal BMI, paternal characteristics, or other covariates, which posed limitations on the analyses. Another important point to note is that the impact of different ART factors on health of offspring has not been addressed. Over the years, ART practices and technologies have continued to evolve, for example, the increasing use of oocyte freezing and embryo biopsy for genetic testing and the shift of slow freezing to vitrification method for gamete or embryo freezing. It has been shown that singleton babies conceived from fresh embryo transfers of IVF are associated with increased risks of low birthweight and preterm delivery, while ART involving frozen embryos are associated with higher incidences of large babies, macrosomia, and hypertensive disorders of pregnancy [10]. Conversely, both low birthweight, intrauterine growth restriction (IUGR), as well as macrosomia have been linked with increased risk of later T2D and CVD [11]. These differential outcomes illustrate that the different ART techniques may have different safety profiles and exert different impacts on the long-term health of offspring. Of note, the study by Norrman and colleagues included relatively few births from frozen embryos, and these have not been compared to births by SC for later risk of diabetes or CVD.This important study highlights some of the challenges in ascertaining long-term effects of ART, or other early life exposures, for that matter. The establishment of ART registries including the important exposure factors may be an important component for the way forward, especially given the long-term follow-up required. There are important challenges, including those around confidentiality, but also the increasingly diverse and complex treatment protocols, as well as innovative technologies, which may be associated with different long-term outcomes. There is currently limited understanding of the long-term outcome of some of these novel techniques. There are also new challenges given the globalization of healthcare delivery, with increasing cross-border reproductive care [12]. The increasing cryopreservation of gametes, gonadal tissues, and embryos will pose new challenges on tracking the outcomes of ART births. More population-based long-term studies are warranted, and establishing the infrastructure that would facilitate anonymous linkage of ART registers, birth records with national diabetes and other disease registers that facilitate tracking of long-term health may be one way forward. Nevertheless, given the sensitivities around the data involved, such analyses may be difficult to perform in some areas, and population-based analyses, wherever possible, will continue to contribute much-needed data to this discussion.