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.     

Haemophilus ducreyi Cutaneous Ulcer Strains Are Nearly Identical to Class I Genital Ulcer Strains

Background

Although cutaneous ulcers (CU) in the tropics is frequently attributed to Treponema pallidum subspecies pertenue, the causative agent of yaws, Haemophilus ducreyi has emerged as a major cause of CU in yaws-endemic regions of the South Pacific islands and Africa. H. ducreyi is generally susceptible to macrolides, but CU strains persist after mass drug administration of azithromycin for yaws or trachoma. H. ducreyi also causes genital ulcers (GU) and was thought to be exclusively transmitted by microabrasions that occur during sex. In human volunteers, the GU strain 35000HP does not infect intact skin; wounds are required to initiate infection. These data led to several questions: Are CU strains a new variant of H. ducreyi or did they evolve from GU strains? Do CU strains contain additional genes that could allow them to infect intact skin? Are CU strains susceptible to azithromycin?

Methodology/Principal Findings

To address these questions, we performed whole-genome sequencing and antibiotic susceptibility testing of 5 CU strains obtained from Samoa and Vanuatu and 9 archived class I and class II GU strains. Except for single nucleotide polymorphisms, the CU strains were genetically almost identical to the class I strain 35000HP and had no additional genetic content. Phylogenetic analysis showed that class I and class II strains formed two separate clusters and CU strains evolved from class I strains. Class I strains diverged from class II strains ~1.95 million years ago (mya) and CU strains diverged from the class I strain 35000HP ~0.18 mya. CU and GU strains evolved under similar selection pressures. Like 35000HP, the CU strains were highly susceptible to antibiotics, including azithromycin.

Conclusions/Significance

These data suggest that CU strains are derivatives of class I strains that were not recognized until recently. These findings require confirmation by analysis of CU strains from other regions.     

The Streptococcal Binding Site in the Gelatin-binding Domain of Fibronectin Is Consistent with a Non-linear Arrangement of Modules

Fibronectin-binding proteins (FnBPs) of Staphylococcus aureus and Streptococcus pyogenes mediate invasion of human endothelial and epithelial cells in a process likely to aid the persistence and/or dissemination of infection. In addition to binding sites for the N-terminal domain (NTD) of fibronectin (Fn), a number of streptococcal FnBPs also contain an upstream region (UR) that is closely associated with an NTD-binding region; UR binds to the adjacent gelatin-binding domain (GBD) of Fn. Previously, UR was shown to be required for efficient streptococcal invasion of epithelial cells. Here we show, using a Streptococcus zooepidemicus FnBP, that the UR-binding site in GBD resides largely in the ⁸F1⁹F1 module pair. We also show that UR inhibits binding of a peptide from the α1 chain of type I collagen to ⁸F1⁹F1 and that UR binding to ⁸F1 is likely to occur through anti-parallel β-zipper formation. Thus, we propose that streptococcal proteins that contain adjacent NTD- and GBD-binding sites form a highly unusual extended tandem β-zipper that spans the two domains and mediates high affinity binding to Fn through a large intermolecular interface. The proximity of the UR- and NTD-binding sequences in streptococcal FnBPs is consistent with a non-linear arrangement of modules in the tertiary structure of the GBD of Fn.     

Initiation of Purinergic Signaling by Exocytosis of ATP-containing Vesicles in Liver Epithelium

Extracellular ATP represents an important autocrine/paracrine signaling molecule within the liver. The mechanisms responsible for ATP release are unknown, and alternative pathways have been proposed, including either conductive ATP movement through channels or exocytosis of ATP-enriched vesicles, although direct evidence from liver cells has been lacking. Utilizing dynamic imaging modalities (confocal and total internal reflection fluorescence microscopy and luminescence detection utilizing a high sensitivity CCD camera) at different scales, including confluent cell populations, single cells, and the intracellular submembrane space, we have demonstrated in a model liver cell line that (i) ATP release is not uniform but reflects point source release by a defined subset of cells; (ii) ATP within cells is localized to discrete zones of high intensity that are ∼1 μm in diameter, suggesting a vesicular localization; (iii) these vesicles originate from a bafilomycin A₁-sensitive pool, are depleted by hypotonic exposure, and are not rapidly replenished from recycling of endocytic vesicles; and (iv) exocytosis of vesicles in response to cell volume changes depends upon a complex series of signaling events that requires intact microtubules as well as phosphoinositide 3-kinase and protein kinase C. Collectively, these findings are most consistent with an essential role for exocytosis in regulated release of ATP and initiation of purinergic signaling in liver cells.     

The Recognition of and Care Seeking Behaviour for Childhood Illness in Developing Countries: A Systematic Review

Background

Pneumonia, diarrhoea, and malaria are among the leading causes of death in children. These deaths are largely preventable if appropriate care is sought early. This review aimed to determine the percentage of caregivers in low- and middle-income countries (LMICs) with a child less than 5 years who were able to recognise illness in their child and subsequently sought care from different types of healthcare providers.

Methods and Findings

We conducted a systematic literature review of studies that reported recognition of, and/or care seeking for episodes of diarrhoea, pneumonia or malaria in LMICs. The review is registered with PROSPERO (registration number: CRD42011001654). Ninety-one studies met the inclusion criteria. Eighteen studies reported data on caregiver recognition of disease and seventy-seven studies on care seeking. The median sensitivity of recognition of diarrhoea, malaria and pneumonia was low (36.0%, 37.4%, and 45.8%, respectively). A median of 73.0% of caregivers sought care outside the home. Care seeking from community health workers (median: 5.4% for diarrhoea, 4.2% for pneumonia, and 1.3% for malaria) and the use of oral rehydration therapy (median: 34%) was low.

Conclusions

Given the importance of this topic to child survival programmes there are few published studies. Recognition of diarrhoea, malaria and pneumonia by caregivers is generally poor and represents a key factor to address in attempts to improve health care utilisation. In addition, considering that oral rehydration therapy has been widely recommended for over forty years, its use remains disappointingly low. Similarly, the reported levels of care seeking from community health workers in the included studies are low even though global action plans to address these illnesses promote community case management. Giving greater priority to research on care seeking could provide crucial evidence to inform child mortality programmes.     

Quantitative real-time RT-PCR demonstrates that handling stress can lead to rapid increases of gill-associated virus (GAV) infection levels in Penaeus monodon

Gill-associated virus (GAV) of the black tiger prawn Penaeus monodon has been implicated as a cause of periodic production losses in Australia since 1996. We report here the development of a real-time quantitative RT-PCR (qRT-PCR) for GAV. A dilution series of in vitro transcribed RNA was used to determine the sensitivity limit of the qRT-PCR and as a standard for GAV quantification. A linear relationship between cycle threshold (Ct) values and input RNA was obtained over a wide concentration range between 4.86 x 10(9) and 0.5 template copies per reaction, the latter being the test detection limit. The qRT-PCR was used to follow the progression of GAV levels in a group of 15 adult male P. monodon with chronic GAV infections that were super-infected by intramuscular injection of an inoculum containing high levels of GAV. By Day 9 post-injection, cumulative mortalities reached 100% (15/15) in the GAV-injected prawns and 40% (2/5) in placebo-injected prawns. Spermatophores were collected at the beginning, and together with other tissues, at the end of the trial. Prawns were also bled at regular intervals to collect circulating haemocytes. The qRT-PCR revealed that GAV loads increased significantly in haemocytes collected from both the control and super-infected prawns (p = 0.010). This increase was significantly higher in the super-infected prawns (p = 0.047). The rapid increase in GAV levels in super-infected P. monodon was expected. However, the increase in the control prawns was not, and indicates that repetitive bleeding and handling stress can stimulate GAV proliferation in chronically infected P. monodon.     

Imidazo[1,2-b]pyridazines: a potent and selective class of cyclin-dependent kinase inhibitors

Modification of imidazo[1,2-a]pyridine CDK inhibitors lead to identification of less lipophilic imidazo[1,2-b]pyridazine series of CDK inhibitors. Although several equivalent compounds from these two series have similar structure and show similar CDK activity, the SAR of the two series differs significantly. Protein inhibitor structure determination has confirmed differences in binding mode and given some understanding of these differences in SAR. Potent and selective imidazo[1,2-b]pyridazine inhibitors of CDK2 have been identified, which show >1 microM plasma levels following a 2mg/kg oral dose to mice.     

Strain variation in an emerging iridovirus of warm-water fishes

Although iridoviruses vary widely within and among genera with respect to their host range and virulence, variation within iridovirus species has been less extensively characterized. This study explores the nature and extent of intraspecific variation within an emerging iridovirus of North American warm-water fishes, largemouth bass virus (LMBV). Three LMBV isolates recovered from three distinct sources differed genetically and phenotypically. Genetically, the isolates differed in the banding patterns generated from amplified fragment length polymorphism analysis but not in their DNA sequences at two loci of different degrees of evolutionary stability. In vitro, the isolates replicated at identical rates in cell culture, as determined by real-time quantitative PCR of viral particles released into suspension. In vivo, the isolates varied over fivefold in virulence, as measured by the rate at which they induced mortality in juvenile largemouth bass. This variation was reflected in the viral loads of exposed fish, measured using real-time quantitative PCR; the most virulent viral strain also replicated to the highest level in fish. Together, these results justify the designation of these isolates as different strains of LMBV. Strain variation in iridoviruses could help explain why animal populations naturally infected with iridovirus pathogens vary so extensively in their clinical responses to infection. The results of this study are especially relevant to emerging iridoviruses of aquaculture systems and wildlife.