Poliovirus type 1 systemic humoral and intestinal mucosal immunity induced by monovalent oral poliovirus vaccine, fractional inactivated poliovirus vaccine, and bivalent oral poliovirus vaccine: A randomized controlled trial.

BACKGROUND: To inform response strategies, we examined type 1 humoral and intestinal immunity induced by 1) one fractional inactivated poliovirus vaccine (fIPV) dose given with monovalent oral poliovirus vaccine (mOPV1), and 2) mOPV1 versus bivalent OPV (bOPV). METHODS: We conducted a randomized, controlled, open-label trial in Dhaka, Bangladesh. Healthy infants aged 5 weeks were block randomized to one of four arms: mOPV1 at age 6-10-14 weeks/fIPV at 6 weeks (A); mOPV1 at 6-10-14 weeks/fIPV at 10 weeks (B); mOPV1 at 6-10-14 weeks (C); and bOPV at 6-10-14 weeks (D). Immune response at 10 weeks and cumulative response at 14 weeks was assessed among the modified intention-to-treat population, defined as seroconversion from seronegative (<1:8 titers) to seropositive (≥1:8) or a four-fold titer rise among seropositive participants sustained to age 18 weeks. We examined virus shedding after two doses of mOPV1 with and without fIPV, and after the first mOPV1 or bOPV dose. The trial is registered at ClinicalTrials.gov (NCT03722004). FINDINGS: During 18 December 2018 - 23 November 2019, 1,192 infants were enrolled (arms A:301; B:295; C:298; D:298). Immune responses at 14 weeks did not differ after two mOPV1 doses alone (94% [95% CI: 91-97%]) versus two mOPV1 doses with fIPV at 6 weeks (96% [93-98%]) or 10 weeks (96% [93-98%]). Participants who received mOPV1 and fIPV at 10 weeks had significantly lower shedding (p < 0·001) one- and two-weeks later compared with mOPV1 alone. Response to one mOPV1 dose was significantly higher than one bOPV dose (79% versus 67%; p < 0·001) and shedding two-weeks later was significantly higher after mOPV1 (76% versus 56%; p < 0·001) indicating improved vaccine replication. Ninety-nine adverse events were reported, 29 serious including two deaths; none were attributed to study vaccines. INTERPRETATION: Given with the second mOPV1 dose, fIPV improved intestinal immunity but not humoral immunity. One mOPV1 dose induced higher humoral and intestinal immunity than bOPV. FUNDING: U.S. Centers for Disease Control and Prevention.

Surveillance To Track Progress Toward Poliomyelitis Eradication - Worldwide, 2021-2022.

Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of wild poliovirus (WPV) cases has declined by >99.9%, and WPV serotypes 2 and 3 have been declared eradicated (1). By the end of 2022, WPV type 1 (WPV1) transmission remained endemic only in Afghanistan and Pakistan (2,3). However, during 2021-2022, Malawi and Mozambique reported nine WPV1 cases that were genetically linked to Pakistan (4,5), and circulating vaccine-derived poliovirus (cVDPV) outbreaks were detected in 42 countries (6). cVDPVs are oral poliovirus vaccine-derived viruses that can emerge after prolonged circulation in populations with low immunity allowing reversion to neurovirulence and can cause paralysis. Polioviruses are detected primarily through surveillance for acute flaccid paralysis (AFP), and poliovirus is confirmed through stool specimen testing. Environmental surveillance, the systematic sampling of sewage and testing for the presence of poliovirus, supplements AFP surveillance. Both surveillance systems were affected by the COVID-19 pandemic's effects on public health activities during 2020 (7,8) but improved in 2021 (9). This report updates previous reports (7,9) to describe surveillance performance during 2021-2022 in 34 priority countries.* In 2022, a total of 26 (76.5%) priority countries met the two key AFP surveillance performance indicator targets nationally compared with 24 (70.6%) countries in 2021; however, substantial gaps remain in subnational areas. Environmental surveillance expanded to 725 sites in priority countries, a 31.1% increase from the 553 sites reported in 2021. High-quality surveillance is critical to rapidly detect poliovirus transmission and enable prompt poliovirus outbreak response to stop circulation. Frequent monitoring of surveillance guides improvements to achieve progress toward polio eradication.

Immunogenicity of novel oral poliovirus vaccine type 2 administered concomitantly with bivalent oral poliovirus vaccine: an open-label, non-inferiority, randomised, controlled trial.

BACKGROUND: Novel oral poliovirus vaccine type 2 (nOPV2) was developed by modifying the Sabin strain to increase genetic stability and reduce risk of seeding new circulating vaccine-derived poliovirus type 2 outbreaks. Bivalent oral poliovirus vaccine (bOPV; containing Sabin types 1 and 3) is the vaccine of choice for type 1 and type 3 outbreak responses. We aimed to assess immunological interference between nOPV2 and bOPV when administered concomitantly. METHODS: We conducted an open-label, non-inferiority, randomised, controlled trial at two clinical trial sites in Dhaka, Bangladesh. Healthy infants aged 6 weeks were randomly assigned (1:1:1) using block randomisation, stratified by site, to receive nOPV2 only, nOPV2 plus bOPV, or bOPV only, at the ages of 6 weeks, 10 weeks, and 14 weeks. Eligibility criteria included singleton and full term (≥37 weeks' gestation) birth and parents intending to remain in the study area for the duration of study follow-up activities. Poliovirus neutralising antibody titres were measured at the ages of 6 weeks, 10 weeks, 14 weeks, and 18 weeks. The primary outcome was cumulative immune response for all three poliovirus types at the age of 14 weeks (after two doses) and was assessed in the modified intention-to-treat population, which was restricted to participants with adequate blood specimens from all study visits. Safety was assessed in all participants who received at least one dose of study product. A non-inferiority margin of 10% was used to compare single and concomitant administration. This trial is registered with ClinicalTrials.gov, NCT04579510. FINDINGS: Between Feb 8 and Sept 26, 2021, 736 participants (244 in the nOPV2 only group, 246 in the nOPV2 plus bOPV group, and 246 in the bOPV only group) were enrolled and included in the modified intention-to-treat analysis. After two doses, 209 (86%; 95% CI 81-90) participants in the nOPV2 only group and 159 (65%; 58-70) participants in the nOPV2 plus bOPV group had a type 2 poliovirus immune response; 227 (92%; 88-95) participants in the nOPV2 plus bOPV group and 229 (93%; 89-96) participants in the bOPV only group had a type 1 response; and 216 (88%; 83-91) participants in the nOPV2 plus bOPV group and 212 (86%; 81-90) participants in the bOPV only group had a type 3 response. Co-administration was non-inferior to single administration for types 1 and 3, but not for type 2. There were 15 serious adverse events (including three deaths, one in each group, all attributable to sudden infant death syndrome); none were attributed to vaccination. INTERPRETATION: Co-administration of nOPV2 and bOPV interfered with immunogenicity for poliovirus type 2, but not for types 1 and 3. The blunted nOPV2 immunogenicity we observed would be a major drawback of using co-administration as a vaccination strategy. FUNDING: The US Centers for Disease Control and Prevention.

Surveillance to Track Progress Toward Polio Eradication - Worldwide, 2020-2021.

Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of reported poliomyelitis cases worldwide has declined by approximately 99.99%. By the end of 2021, wild poliovirus (WPV) remained endemic in only two countries (Pakistan and Afghanistan). However, a WPV type 1 (WPV1) case with paralysis onset in 2021, was reported by Malawi a year after the World Health Organization (WHO) African Region (AFR) was certified as WPV-free and circulating vaccine-derived poliovirus (cVDPV) cases were reported from 31 countries during 2020-2021 (1,2). cVDPVs are oral poliovirus vaccine-derived viruses that can emerge after prolonged circulation in populations with low immunity and cause paralysis. The primary means of detecting poliovirus transmission is through surveillance for acute flaccid paralysis (AFP) among persons aged <15 years, with confirmation through stool specimen testing by WHO-accredited laboratories, supplemented by systematic sampling of sewage and testing for the presence of poliovirus (environmental surveillance). The COVID-19 pandemic caused disruptions in polio vaccination and surveillance activities across WHO regions in 2020; during January-September 2020, the number of reported cases of AFP declined and the interval between stool collection and receipt by laboratories increased compared with the same period in 2019 (3). This report summarizes surveillance performance indicators for 2020 and 2021 in 43 priority countries* and updates previous reports (4). In 2021, a total of 32 (74%) priority countries† met two key surveillance performance indicator targets nationally, an improvement from 2020 when only 23 (53%) met both targets; however, substantial national and subnational gaps persist. High-performing poliovirus surveillance is critical to tracking poliovirus transmission. Frequent monitoring of surveillance indicators could help identify gaps, guide improvements, and enhance the overall sensitivity and timelines of poliovirus detection to successfully achieve polio eradication.

Progress Toward Polio Eradication - Worldwide, January 2019-June 2021.

In 1988, when the Global Polio Eradication Initiative (GPEI) began, polio paralyzed >350,000 children across 125 countries. Today, only one of three wild poliovirus serotypes, type 1 (WPV1), remains in circulation in only two countries, Afghanistan and Pakistan. This report summarizes progress toward global polio eradication during January 1, 2019-June 30, 2021 and updates previous reports (1,2). In 2020, 140 cases of WPV1 were reported, including 56 in Afghanistan (a 93% increase from 29 cases in 2019) and 84 in Pakistan (a 43% decrease from 147 cases in 2019). As GPEI focuses on the last endemic WPV reservoirs, poliomyelitis outbreaks caused by circulating vaccine-derived poliovirus (cVDPV) have emerged as a result of attenuated oral poliovirus vaccine (OPV) virus regaining neurovirulence after prolonged circulation in underimmunized populations (3). In 2020, 32 countries reported cVDPV outbreaks (four type 1 [cVDPV1], 26 type 2 [cVDPV2] and two with outbreaks of both); 13 of these countries reported new outbreaks. The updated GPEI Polio Eradication Strategy 2022-2026 (4) includes expanded use of the type 2 novel oral poliovirus vaccine (nOPV2) to avoid new emergences of cVDPV2 during outbreak responses (3). The new strategy deploys other tactics, such as increased national accountability, and focused investments for overcoming the remaining barriers to eradication, including program disruptions and setbacks caused by the COVID-19 pandemic.

Surveillance to Track Progress Toward Polio Eradication - Worldwide, 2019-2020.

When the Global Polio Eradication Initiative (GPEI) was established in 1988, an estimated 350,000 poliomyelitis cases were reported worldwide. In 2020, 140 wild poliovirus (WPV) cases were confirmed, representing a 99.99% reduction since 1988. WPV type 1 transmission remains endemic in only two countries (Pakistan and Afghanistan), but outbreaks of circulating vaccine-derived poliovirus (cVDPV) occurred in 33 countries during 2019-2020 (1,2). Poliovirus transmission is detected primarily through syndromic surveillance for acute flaccid paralysis (AFP) among children aged <15 years, with confirmation by laboratory testing of stool specimens. Environmental surveillance supplements AFP surveillance and plays an increasingly important role in detecting poliovirus transmission. Within 2 weeks of COVID-19 being declared a global pandemic (3), GPEI recommended continuing surveillance activities with caution and paused all polio supplementary immunization activities (4). This report summarizes surveillance performance indicators for 2019 and 2020 in 42 priority countries at high risk for poliovirus transmission and updates previous reports (5). In 2020, 48% of priority countries* in the African Region, 90% in the Eastern Mediterranean Region, and 40% in other regions met AFP surveillance performance indicators nationally. The number of priority countries rose from 40 in 2019 to 42 in 2020.† Analysis of 2019-2020 AFP surveillance data from 42 countries at high risk for poliovirus transmission indicates that national and subnational nonpolio AFP rates and stool specimen adequacy declined in many priority countries, particularly in the African Region, suggesting a decline in surveillance sensitivity and quality. The findings in this report can be used to guide improvements to restore a sensitive surveillance system that can track poliovirus transmission and provide evidence of interruption of transmission.

Health and Demographic Surveillance Systems Within the Child Health and Mortality Prevention Surveillance Network.

Health and demographic surveillance systems (HDSSs) provide a foundation for characterizing and defining priorities and strategies for improving population health. The Child Health and Mortality Prevention Surveillance (CHAMPS) project aims to inform policy to prevent child deaths through generating causes of death from surveillance data combined with innovative diagnostic and laboratory methods. Six of the 7 sites that constitute the CHAMPS network have active HDSSs: Mozambique, Mali, Ethiopia, Kenya, Bangladesh, and South Africa; the seventh, in Sierra Leone, is in the early planning stages. This article describes the network of CHAMPS HDSSs and their role in the CHAMPS project. To generate actionable health and demographic data to prevent child deaths, the network depends on reliable demographic surveillance, and the HDSSs play this crucial role.

Reporting Deaths Among Children Aged <5 Years After the Ebola Virus Disease Epidemic - Bombali District, Sierra Leone, 2015-2016.

Mortality surveillance and vital registration are limited in Sierra Leone, a country with one of the highest mortality rates among children aged <5 years worldwide, approximately 120 deaths per 1,000 live births (1,2). To inform efforts to strengthen surveillance, stillbirths and deaths in children aged <5 years from multiple surveillance streams in Bombali Sebora chiefdom were retrospectively reviewed. In total, during January 2015-November 2016, 930 deaths in children aged <5 years were identified, representing 73.3% of the 1,269 deaths that were expected based on modeled estimates. The "117" telephone alert system established during the Ebola virus disease (Ebola) epidemic captured 683 (73.4%) of all reported deaths in children aged <5 years, and was the predominant reporting source for stillbirths (n = 172). In the absence of complete vital events registration, 117 call alerts markedly improved the completeness of reporting of stillbirths and deaths in children aged <5 years.

Longitudinal analysis of mature breastmilk and serum immune composition among mixed HIV-status mothers and their infants.

BACKGROUND & AIMS: Understanding mature breastmilk immunology may benefit infants chronically exposed to infectious pathogens in resource-limited regions. METHODS: This prospective rural/semi-rural Tanzanian cohort of women (n = 102 at delivery; 38% HIV-positive) and their infants (n = 102) investigated breastmilk, maternal and infant serum immunoglobulins (IgA/IgG1-4/IgM) and cytokines (IL-1ß/IL-2/IL-6/IL-10/IL-12p70/IL-13/IL-15/TNF-α/IFN-γ) at 1, 2, 3, 6-months postpartum. RESULTS: Milk immunoglobulins followed an inverse U-shaped pattern, while cytokine patterns were mixed. Exclusive breastfeeding duration and feeding intensity were associated with greater breastmilk total immunoglobulin and IgA, IgG1-3 and IL-12p70 concentrations. Maternal mastitis, fever or cough was associated with higher breastmilk total cytokine concentrations, while infant fever was associated with lower milk immunoglobulins or cytokines. Strong (r ≥ 0.40) to weak (r = 0.20-0.29) positive correlations between maternal serum-breastmilk or breastmilk-infant serum immunoglobulins were evident. Breastmilk cytokines were moderate to weakly negatively correlated with infant serum. Breastmilk immunology did not differ by maternal malnutrition or HIV-seropositivity. CONCLUSIONS: Mature breastmilk is a dynamic source of many specific and non-specific immune factors associated with maternal and infant health and infant nutrition. Breastfeeding practices are associated with differential breastmilk immunological composition providing immunological support for universal recommendations to exclusively breastfeed for 6-months.

Associations between gestational anthropometry, maternal HIV, and fetal and early infancy growth in a prospective rural/semi-rural Tanzanian cohort, 2012-13.

BACKGROUND: Healthcare access and resources differ considerably between urban and rural settings making cross-setting generalizations difficult. In resource-restricted rural/semi-rural environments, identification of feasible screening tools is a priority. The objective of this study was to evaluate gestational anthropometry in relation to birth and infant growth in a rural/semi-rural Tanzanian prospective cohort of mothers and their infants. METHODS: Mothers (n = 114: 44 HIV-positive) attending antenatal clinic visits were recruited in their second or third trimester between March and November, 2012, and followed with their infants through 6-months post-partum. Demographic, clinical, and infant feeding data were obtained using questionnaires administered by a Swahili-speaking research nurse on demographic, socioeconomic, clinical, and infant feeding practices. Second or third trimester anthropometry (mid-upper arm circumference [MUAC], triceps skinfold thickness, weight, height), pregnancy outcomes, birth (weight, length, head circumference) and infant anthropometry (weight-for-age z-score [WAZ], length-for-age z-score [LAZ]) were obtained. Linear regression and mixed effect modeling were used to evaluate gestational factors in relation to pregnancy and infant outcomes. RESULTS AND DISCUSSION: Gestational MUAC and maternal HIV status (HIV-positive mothers = 39%) were associated with infant WAZ and LAZ from birth to 6-months in multivariate models, even after adjustment for infant feeding practices. The lowest gestational MUAC tertile was associated with lower WAZ throughout early infancy, as well as lower LAZ at 3 and 6-months. In linear mixed effects models through 6-months, each 1 cm increase in gestational MUAC was associated with a 0.11 increase in both WAZ (P < 0.001) and LAZ (P = 0.001). Infant HIV-exposure was negatively associated with WAZ (ß = -0.65, P < 0.001) and LAZ (ß = -0.49, P < 0.012) from birth to 6-months. CONCLUSIONS: Lower gestational MUAC, evaluated using only a tape measure and minimal training that is feasible in non-urban clinic and community settings, was associated with lower infant anthropometric measurements. In this rural and semi-rural setting, HIV-exposure was associated with poorer anthropometry through 6-months despite maternal antiretroviral access. Routine assessment of MUAC has the potential to identify at-risk women in need of additional health interventions designed to optimize pregnancy outcomes and infant growth. Further research is needed to establish gestational MUAC reference ranges and to define interventions that successfully improve MUAC during pregnancy.

Cryptosporidium prevalence and risk factors among mothers and infants 0 to 6 months in rural and semi-rural Northwest Tanzania: a prospective cohort study.

BACKGROUND: Cryptosporidium epidemiology is poorly understood, but infection is suspected of contributing to childhood malnutrition and diarrhea-related mortality worldwide. METHODS/FINDINGS: A prospective cohort of 108 women and their infants in rural/semi-rural Tanzania were followed from delivery through six months. Cryptosporidium infection was determined in feces using modified Ziehl-Neelsen staining. Breastfeeding/infant feeding practices were queried and anthropometry measured. Maternal Cryptosporidium infection remained high throughout the study (monthly proportion = 44 to 63%). Infection did not differ during lactation or by HIV-serostatus, except that a greater proportion of HIV-positive mothers were infected at Month 1. Infant Cryptosporidium infection remained undetected until Month 2 and uncommon through Month 3 however, by Month 6, 33% of infants were infected. There were no differences in infant infection by HIV-exposure. Overall, exclusive breastfeeding (EBF) was limited, but as the proportion of infants exclusively breastfed declined from 32% at Month 1 to 4% at Month 6, infant infection increased from 0% at Month 1 to 33% at Month 6. Maternal Cryptosporidium infection was associated with increased odds of infant infection (unadjusted OR = 3.18, 95% CI 1.01 to 9.99), while maternal hand washing prior to infant feeding was counterintuitively also associated with increased odds of infant infection (adjusted OR = 5.02, 95% CI = 1.11 to 22.78). CONCLUSIONS: Both mothers and infants living in this setting suffer a high burden of Cryptosporidium infection, and the timing of first infant infection coincides with changes in breastfeeding practices. It is unknown whether this is due to breastfeeding practices reducing pathogen exposure through avoidance of contaminated food/water consumption; and/or breast milk providing important protective immune factors. Without a Cryptosporidium vaccine, and facing considerable diagnostic challenges and ineffective treatment in young infants, minimizing the overall environmental burden (e.g. contaminated water) and particularly, maternal Cryptosporidium infection burden as a means to protect against early infant infection needs prioritization.