A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial.

BACKGROUND: Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children. METHODS: This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia. To be eligible, all participants had to be healthy according to prespecified criteria, aged 18-40 years for the adult cohort, 15-18 months for toddlers, or 9-10 months for infants, and to be available for visits throughout the follow-up period. The three age cohorts were randomly assigned in a 2:1 ratio (adults) or 1:1 ratio (toddlers and infants) to receive either an MRV-MNP (Micron Biomedical, Atlanta, GA, USA) and a placebo (0·9% sodium chloride) subcutaneous injection, or a placebo-MNP and an MRV subcutaneous injection (MRV-SC; Serum Institute of India, Pune, India). Unmasked staff ransomly assigned the participants using an online application, and they prepared visually identical preparations of the MRV-MNP or placebo-MNP and MRV-SC or placebo-SC, but were not involved in collecting endpoint data. Staff administering the study interventions, participants, parents, and study staff assessing trial endpoints were masked to treatment allocation. The safety population consists of all vaccinated participants, and analysis was conducted according to route of MRV administration, irrespective of subsequent protocol deviations. The immunogenicity population consisted of all vaccinated participants who had a baseline and day 42 visit result available, and who had no protocol deviations considered to substantially affect the immunogenicity endpoints. Solicited local and systemic adverse events were collected for 14 days following vaccination. Unsolicited adverse events were collected to day 180. Age de-escalation between cohorts was based on the review of the safety data to day 14 by an independent data monitoring committee. Serum neutralising antibodies to measles and rubella were measured at baseline, day 42, and day 180. Analysis was descriptive and included safety events, seroprotection and seroconversion rates, and geometric mean antibody concentrations. The trial was registered with the Pan African Clinical Trials Registry PACTR202008836432905, and is complete. FINDINGS: Recruitment took place between May 18, 2021, and May 27, 2022. 45 adults, 120 toddlers, and 120 infants were randomly allocated and vaccinated. There were no safety concerns in the first 14 days following vaccination in either adults or toddlers, and age de-escalation proceeded accordingly. In infants, 93% (52/56; 95% CI 83·0-97·2) seroconverted to measles and 100% (58/58; 93·8-100) seroconverted to rubella following MRV-MNP administration, while 90% (52/58; 79·2-95·2) and 100% (59/59; 93·9-100) seroconverted to measles and rubella respectively, following MRV-SC. Induration at the MRV-MNP application site was the most frequent local reaction occurring in 46 (77%) of 60 toddlers and 39 (65%) of 60 infants. Related unsolicited adverse events, most commonly discolouration at the application site, were reported in 35 (58%) of 60 toddlers and 57 (95%) of 60 infants that had received the MRV-MNP. All local reactions were mild. There were no related severe or serious adverse events. INTERPRETATION: The safety and immunogenicity data support the accelerated development of the MRV-MNP. FUNDING: Bill & Melinda Gates Foundation.

Tolerability, safety, and immunogenicity of the novel oral polio vaccine type 2 in children aged 6 weeks to 59 months in an outbreak response campaign in The Gambia: an observational cohort study.

BACKGROUND: Novel oral polio vaccine type 2 (nOPV2) has been used to interrupt circulating vaccine-derived poliovirus type 2 outbreaks following its WHO emergency use listing. This study reports data on the safety and immunogenicity of nOPV2 over two rounds of a campaign in The Gambia. METHODS: This observational cohort study collected baseline symptoms (vomiting, diarrhoea, irritability, reduced feeding, and reduced activity) and axillary temperature from children aged 6 weeks to 59 months in The Gambia before a series of two rounds of a nOPV2 campaign that took place on Nov 20-26, 2021, and March 19-22, 2022. Serum and stool samples were collected from a subset of the participants. The same symptoms were re-assessed during the week following each dose of nOPV2. Stool samples were collected on days 7 and 28, and serum was collected on day 28 following each dose. Adverse events, including adverse events of special interest, were documented for 28 days after each campaign round. Serum neutralising antibodies were measured by microneutralisation assay, and stool poliovirus excretion was measured by real-time RT-PCR. FINDINGS: Of the 5635 children eligible for the study, 5504 (97·7%) received at least one dose of nOPV2. There was no increase in axillary temperature or in any of the baseline symptoms following either rounds of the campaigns. There were no adverse events of special interest and no other safety signals of concern. Poliovirus type 2 seroconversion rates were 70% (95% CI 62 to 78; 87 of 124 children) following one dose of nOPV2 and 91% (85 to 95; 113 of 124 children) following two doses. Poliovirus excretion on day 7 was lower after the second round (162 of 459 samples; 35·3%, 95% CI 31·1 to 39·8) than after the first round (292 of 658 samples; 44·4%, 40·6 to 48·2) of the campaign (difference -9·1%; 95% CI -14·8 to -3·3), showing the induction of mucosal immunity. INTERPRETATION: In a campaign in west Africa, nOPV2 was well tolerated and safe. High rates of seroconversion and evidence of mucosal immunity support the licensure and WHO prequalification of this vaccine. FUNDING: Bill & Melinda Gates Foundation.

Anti-merozoite antibodies induce natural killer cell effector function and are associated with immunity against malaria.

Natural killer (NK) cells are potent immune effectors that can be activated via antibody-mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that NK cells degranulate and release IFN-γ upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK (Ab-NK) activity was largely strain transcending and enhanced invasion inhibition into erythrocytes. Ab-NK was associated with the successful control of parasitemia after experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent P. falciparum infections, and was associated with a lower risk of clinical episodes of malaria. Nine of the 14 vaccine candidates tested induced Ab-NK, including some less well-characterized antigens: P41, P113, MSP11, RHOPH3, and Pf_11363200. These data highlight an important role of Ab-NK activity in immunity against malaria and provide a potential mechanism for evaluating vaccine candidates.

Entomological impact of mass administration of ivermectin and dihydroartemisinin-piperaquine in The Gambia: a cluster-randomized controlled trial.

BACKGROUND: Vector control interventions in sub-Saharan Africa rely on insecticide-treated nets and indoor residual spraying. Insecticide resistance, poor coverage of interventions, poor quality nets and changes in vector behavior threaten the effectiveness of these interventions and, consequently, alternative tools are needed. Mosquitoes die after feeding on humans or animals treated with ivermectin (IVM). Mass drug administration (MDA) with IVM could reduce vector survival and decrease malaria transmission. The entomological impact of MDA of combined IVM and dihydroartemisinin-piperaquine was assessed in a community-based, cluster-randomized trial. METHODS: A cluster-randomized trial was implemented in 2018 and 2019 in 32 villages in the Upper River Region, The Gambia. The with the inhabitants of 16 intervention villages eligible to receive three monthly rounds of MDA at the beginning of the malaria transmission season. Entomological surveillance with light traps and human landing catches (HLC) was carried out during a 7- to 14-day period after each round of MDA, and then monthly until the end of the year. The mosquitocidal effect of IVM was determined by direct membrane feeding assays. RESULTS: Of the 15,017 mosquitoes collected during the study period, 99.65% (n = 14,965) were Anopheles gambiae sensu lato (An. gambiae s.l.), comprising Anopheles arabiensis (56.2%), Anopheles coluzzii (24.5%), Anopheles gambiae sensu stricto (An. gembiae s.s.; 16.0%) and Anopheles funestus sensu lato (An. funestus s.l.; 0.35%). No effect of the intervention on vector parity was observed. Vector density determined on light trap collections was significantly lower in the intervention villages in 2019 (adjusted incidence rate ratio: 0.39; 95% confidence interval [CI]: 0.20, 0.74; P = 0.005) but not in 2018. However, vector density determined in HLC collections was similar in both the intervention and control villages. The entomological inoculation rate was significantly lower in the intervention villages than in the control villages (odds ratio: 0.36, 95% CI: 0.19, 0.70; P = 0·003). Mosquito mortality was significantly higher when blood fed on IVM-treated individuals up to 21 days post-treatment, particularly in adults and individuals with a higher body mass index. CONCLUSION: Mass drug administration with IVM decreased vector density and the entomological inoculation rate while the effect on vector parity was less clear. Survival of mosquitoes fed on blood collected from IVM-treated individuals was significantly lower than that in mosquitoes which fed on controls. The influence of host characteristics on mosquito survivorship indicated that dose optimization could improve IVM efficacy. Future detailed entomological evaluation trials in which IVM is administered as stand-alone intervention may elucidate the contribution of this drug to the observed reduction in transmission.

Tracking the uptake and trajectory of COVID-19 vaccination coverage in 15 West African countries: an interim analysis.

The African Union Bureau of Heads of State and Government endorsed the COVID-19 Vaccine Development and Access Strategy to vaccinate at least 60% of each country's population with a safe and efficacious vaccine by 2022, to achieve the population-level immunity needed to bring the pandemic under control. Using publicly available, country-level population estimates and COVID-19 vaccination data, we provide unique insights into the uptake trends of COVID-19 vaccinations in the 15 countries that comprise the Economic Community of West Africa States (ECOWAS). Based on the vaccination rates in the ECOWAS region after three months of commencing COVID-19 vaccinations, we provide a projection of the trajectory and speed of vaccination needed to achieve a COVID-19 vaccination coverage rate of at least 60% of the total ECOWAS population. After three months of the deployment of COVID-19 vaccines across the ECOWAS countries, only 0.27% of the region's total population had been fully vaccinated. If ECOWAS countries follow this trajectory, the sub-region will have less than 1.6% of the total population fully vaccinated after 18 months of vaccine deployment. Our projection shows that to achieve a COVID-19 vaccination coverage of at least 60% of the total population in the ECOWAS sub-region after 9, 12 and 18 months of vaccine deployment; the speed of vaccination must be increased to 10, 7 and 4 times the current trajectory, respectively. West African governments must deploy contextually relevant and culturally acceptable strategies for COVID-19 vaccine procurements, distributions and implementations in order to achieve reasonable coverage and save lives, sooner rather than later.

Effect of strikes by health workers on mortality between 2010 and 2016 in Kilifi, Kenya: a population-based cohort analysis.

BACKGROUND: Health workers' strikes are a global occurrence. Kenya has had several strikes by health workers in recent years but their effect on mortality is unknown. We assessed the effect on mortality of six strikes by health workers that occurred from 2010 to 2016 in Kilifi, Kenya. METHODS: Using daily mortality data obtained from the Kilifi Health and Demographic Surveillance System, we fitted a negative binomial regression model to estimate the change in mortality during strike periods and in the 2 weeks immediately after strikes. We did subgroup analyses by age, cause of death, and strike week. FINDINGS: Between Jan 1, 2010, and Nov 30, 2016, we recorded 1 829 929 person-years of observation, 6396 deaths, and 128 strike days (median duration of strikes, 18·5 days [range 9-42]). In the primary analysis, no change in all-cause mortality was noted during strike periods (adjusted rate ratio [RR] 0·93, 95% CI 0·81-1·08; p=0·34). Weak evidence was recorded of variation in mortality rates by age group, with an apparent decrease among infants aged 1-11 months (adjusted RR 0·58, 95% CI 0·33-1·03; p=0·064) and an increase among children aged 12-59 months (1·75, 1·11-2·76; p=0·016). No change was noted in mortality rates in post-strike periods and for any category of cause of death. INTERPRETATION: The brief strikes by health workers during the period 2010-16 were not associated with obvious changes in overall mortality in Kilifi. The combined effects of private (and some public) health care during strike periods, a high proportion of out-of-hospital deaths, and a low number of events might have led us to underestimate the effect. FUNDING: Wellcome Trust and MRC Tropical Epidemiology Group.

Carriage and Acquisition of Extended-spectrum ß-Lactamase-producing Enterobacterales Among Neonates Admitted to Hospital in Kilifi, Kenya.

BACKGROUND: Infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) among hospitalized neonates in sub-Saharan Africa pose significant clinical challenges. Data on prevalence and acquisition of ESBL-E carriage among hospitalized neonates in the region are few, and risk factors for transmission are not clearly defined. METHODS: In a cohort study of consecutive neonatal admissions to Kilifi County Hospital from July 2013 through August 2014, we estimated ESBL-E carriage prevalence on admission using rectal swab cultures and identified risk factors using logistic regression. Using twice-weekly follow-up swabs, we estimated the incidence and identified risk factors for ESBL-E acquisition in hospital using Poisson regression. RESULTS: The prevalence of ESBL-E carriage at admission was 10% (59/569). Cesarean delivery, older neonatal age, and smaller household size were significant risk factors. Of the 510 infants admitted without ESBL-E carriage, 238 (55%) acquired carriage during their hospital stay. The incidence of acquisition was 21.4% (95% confidence interval, 19.0%-24.0%) per day. The rate was positively associated with the number of known neonatal ESBL-E carriers and with the total number of neonates on the same ward. CONCLUSIONS: Carriage of ESBL-E was common among neonates on admission, and in-hospital acquisition was rapid. The dissemination and selection of ESBL-E appears to be driven by hospital exposures, operative delivery, and neonatal ward patient density. Further attention to infection control, patient crowding, and carriage surveillance is warranted.

Effect of 10-valent pneumococcal conjugate vaccine on the incidence of radiologically-confirmed pneumonia and clinically-defined pneumonia in Kenyan children: an interrupted time-series analysis.

BACKGROUND: Pneumococcal conjugate vaccines (PCV) are highly protective against invasive pneumococcal disease caused by vaccine serotypes, but the burden of pneumococcal disease in low-income and middle-income countries is dominated by pneumonia, most of which is non-bacteraemic. We examined the effect of 10-valent PCV on the incidence of pneumonia in Kenya. METHODS: We linked prospective hospital surveillance for clinically-defined WHO severe or very severe pneumonia at Kilifi County Hospital, Kenya, from 2002 to 2015, to population surveillance at Kilifi Health and Demographic Surveillance System, comprising 45 000 children younger than 5 years. Chest radiographs were read according to a WHO standard. A 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PCV10) was introduced in Kenya in January, 2011. In Kilifi, there was a three-dose catch-up campaign for infants (aged <1 year) and a two-dose catch-up campaign for children aged 1-4 years, between January and March, 2011. We estimated the effect of PCV10 on the incidence of clinically-defined and radiologically-confirmed pneumonia through interrupted time-series analysis, accounting for seasonal and temporal trends. FINDINGS: Between May 1, 2002 and March 31, 2015, 44 771 children aged 2-143 months were admitted to Kilifi County Hospital. We excluded 810 admissions between January and March, 2011, and 182 admissions during nurses' strikes. In 2002-03, the incidence of admission with clinically-defined pneumonia was 2170 per 100 000 in children aged 2-59 months. By the end of the catch-up campaign in 2011, 4997 (61·1%) of 8181 children aged 2-11 months had received at least two doses of PCV10 and 23 298 (62·3%) of 37 416 children aged 12-59 months had received at least one dose. Across the 13 years of surveillance, the incidence of clinically-defined pneumonia declined by 0·5% per month, independent of vaccine introduction. There was no secular trend in the incidence of radiologically-confirmed pneumonia over 8 years of study. After adjustment for secular trend and season, incidence rate ratios for admission with radiologically-confirmed pneumonia, clinically-defined pneumonia, and diarrhoea (control condition), associated temporally with PCV10 introduction and the catch-up campaign, were 0·52 (95% CI 0·32-0·86), 0·73 (0·54-0·97), and 0·63 (0·31-1·26), respectively. Immediately before PCV10 was introduced, the annual incidence of clinically-defined pneumonia was 1220 per 100 000; this value was reduced by 329 per 100 000 at the point of PCV10 introduction. INTERPRETATION: Over 13 years, admissions to Kilifi County Hospital for clinically-defined pneumonia decreased sharply (by 27%) in association with the introduction of PCV10, as did the incidence of radiologically-confirmed pneumonia (by 48%). The burden of hospital admissions for childhood pneumonia in Kilifi, Kenya, has been reduced substantially by the introduction of PCV10. FUNDING: Gavi, The Vaccine Alliance and Wellcome Trust.

Invasive Salmonellosis in Kilifi, Kenya.

BACKGROUND: Invasive salmonelloses are a major cause of morbidity and mortality in Africa, but the incidence and case fatality of each disease vary markedly by region. We aimed to describe the incidence, clinical characteristics, and antimicrobial susceptibility patterns of invasive salmonelloses among children and adults in Kilifi, Kenya. METHODS: We analyzed integrated clinical and laboratory records for patients presenting to the Kilifi County Hospital between 1998 and 2014. We calculated incidence, and summarized clinical features and multidrug resistance. RESULTS: Nontyphoidal Salmonella (NTS) accounted for 10.8% and 5.8% of bacteremia cases in children and adults, respectively, while Salmonella Typhi accounted for 0.5% and 2.1%, respectively. Among 351 NTS isolates serotyped, 160 (45.6%) were Salmonella Enteritidis and 152 (43.3%) were Salmonella Typhimurium. The incidence of NTS in children aged <5 years was 36.6 per 100 000 person-years, being highest in infants aged <7 days (174/100 000 person-years). The overall incidence of NTS in children varied markedly by location and declined significantly during the study period; the pattern of dominance of the NTS serotypes also shifted from Salmonella Enteritidis to Salmonella Typhimurium. Risk factors for invasive NTS disease were human immunodeficiency virus infection, malaria, and malnutrition; the case fatality ratio was 22.1% (71/321) in children aged <5 years and 36.7% (11/30) in adults. Multidrug resistance was present in 23.9% (84/351) of NTS isolates and 46.2% (12/26) of Salmonella Typhi isolates. CONCLUSIONS: In Kilifi, the incidence of invasive NTS was high, especially among newborn infants, but typhoid fever was uncommon. NTS remains an important cause of bacteremia in children <5 years of age.