Lessons from the first clinical trial of a non-licensed vaccine among Ugandan adolescents: a phase II field trial of the tuberculosis candidate vaccine, MVA85A

Background: A more effective vaccine for tuberculosis (TB) is a global public health priority. Vaccines under development will always need evaluation in endemic settings, most of which have limited resources. Adolescents are an important target population for a new TB vaccine and for other vaccines which are relevant at school-age. However, in most endemic settings there is limited experience of trials of investigational products among adolescents, and adolescents are not routinely vaccinated. Methods: We used Modified vaccinia Ankara-expressing Ag85A (MVA85A), a well-tolerated candidate vaccine for tuberculosis, to assess the effect of Schistosoma mansoni infection on vaccine immunogenicity among Ugandan adolescents in primary school. We describe here the challenges and lessons learned in designing and implementing this first clinical trial among Ugandan adolescents using a non-licensed vaccine. Results: The school based immunization study was feasible and adhered to Good Clinical Practice principles.  Engagement with the community and all stakeholders was critical for successful implementation of the trial. Creative and adaptable strategies were used to address protocol-specific, operational and logistical challenges. This study provided lessons and solutions that can be applied to other trials among adolescents in similar settings elsewhere, and to school-based immunization programs. Conclusion: Sufficient time and resources should be planned for community preparation and sensitization to ensure buy in and acceptance of a project of this kind. This trial shows that challenges to implementing early field trials in Africa are not insurmountable and that necessary well-planned high-quality ethical trials are feasible and should be encouraged. Trial Registration: ClinicalTrials.gov NCT02178748 03/06/201

The Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA): study protocol for a randomised controlled trial.

BACKGROUND: The Hygiene Hypothesis proposes that infection exposure protects against inflammatory conditions. Helminths possess allergen-like molecules and may specifically modulate allergy-related immunological pathways to inhibit responses which protect against them. Mass drug administration is recommended for helminth-endemic communities to control helminth-induced pathology, but may also result in increased rates of inflammation-mediated diseases in resource-poor settings. Immunological studies integrated with implementation of helminth control measures may elucidate how helminth elimination contributes to ongoing epidemics of inflammatory diseases. We present the design of the Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA), a cluster-randomised trial evaluating the risks and benefits of intensive versus standard anthelminthic treatment for allergy-related diseases and other health outcomes. METHODS/DESIGN: The setting is comprised of island fishing communities in Mukono district, Uganda. Twenty-six communities have been randomised in a 1:1 ratio to receive standard or intensive anthelminthic intervention for a three-year period. Baseline characteristics were collected immediately prior to intervention rollout, commenced in February 2013. Primary outcomes are reported wheeze in the past 12 months and atopy (skin prick test response and allergen-specific immunoglobulin (asIg) E concentration). Secondary outcomes are visible flexural dermatitis, helminth infections, haemoglobin, growth parameters, hepatosplenomegaly, and responses to vaccine antigens. The trial provides a platform for in-depth analysis of clinical and immunological consequences of the contrasting interventions. DISCUSSION: The baseline survey has been completed successfully in a challenging environment. Baseline characteristics were balanced between trial arms. Prevalence of Schistosoma mansoni, hookworm, Strongyloides stercoralis and Trichuris trichiura was 52%, 23%, 13%, and 12%, respectively; 31% of Schistosoma mansoni infections were heavy (>400 eggs/gram). The prevalence of reported wheeze and positive skin prick test to any allergen was 5% and 20%, respectively. Respectively, 77% and 87% of participants had Dermatophagoides- and German cockroach-specific IgE above 0.35 kUA/L. These characteristics suggest that the LaVIISWA study will provide an excellent framework for investigating beneficial and detrimental effects of worms and their treatment, and the mechanisms of such effects. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN47196031) on 7 September 2012

Safety and immunogenicity of ChAdOx1 85A prime followed by MVA85A boost compared with BCG revaccination among Ugandan adolescents who received BCG at birth: a randomised, open-label trial

Background BCG confers reduced, variable protection against pulmonary tuberculosis. A more effective vaccine is needed. We evaluated the safety and immunogenicity of candidate regimen ChAdOx1 85A–MVA85A compared with BCG revaccination among Ugandan adolescents. Methods After ChAdOx1 85A dose escalation and age de-escalation, we did a randomised open-label phase 2a trial among healthy adolescents aged 12–17 years, who were BCG vaccinated at birth, without evident tuberculosis exposure, in Entebbe, Uganda. Participants were randomly assigned (1:1) using a block size of 6, to ChAdOx1 85A followed by MVA85A (on day 56) or BCG (Moscow strain). Laboratory staff were masked to group assignment. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 28 and serious adverse events (SAEs) throughout the trial; and IFN-γ ELISpot response to antigen 85A (day 63 [geometric mean] and days 0–224 [area under the curve; AUC). Findings Six adults (group 1, n=3; group 2, n=3) and six adolescents (group 3, n=3; group 4, n=3) were enrolled in the ChAdOx1 85A-only dose-escalation and age de-escalation studies (July to August, 2019). In the phase 2a trial, 60 adolescents were randomly assigned to ChAdOx1 85A–MVA85A (group 5, n=30) or BCG (group 6, n=30; December, 2019, to October, 2020). All 60 participants from groups 5 and 6 were included in the safety analysis, with 28 of 30 from group 5 (ChAdOx1 85A–MVA85A) and 29 of 30 from group 6 (BCG revaccination) analysed for immunogenicity outcomes. In the randomised trial, 60 AEs were reported among 23 (77%) of 30 participants following ChAdOx1 85A–MVA85A, 31 were systemic, with one severe event that occurred after the MVA85A boost that was rapidly self-limiting. All 30 participants in the BCG revaccination group reported at least one mild to moderate solicited AE; most were local reactions. There were no SAEs in either group. Ag85A-specific IFN-γ ELISpot responses peaked on day 63 in the ChAdOx1 85A–MVA85A group and were higher in the ChAdOx1 85A-MVA85A group compared with the BCG revaccination group (geometric mean ratio 30·59 [95% CI 17·46–53·59], p<0·0001, day 63; AUC mean difference 57 091 [95% CI 40 524–73 658], p<0·0001, days 0–224). Interpretation The ChAdOx1 85A–MVA85A regimen was safe and induced stronger Ag85A-specific responses than BCG revaccination. Our findings support further development of booster tuberculosis vaccines. Funding UK Research and Innovations and Medical Research Council. Translations For the Swahili and Luganda translations of the abstract see Supplementary Materials section

Are birthweight and postnatal weight gain in childhood associated with blood pressure in early adolescence? Results from a Ugandan birth cohort.

BACKGROUND: In Africa, where low birthweight (LBW), malnutrition and high blood pressure (BP) are prevalent, the relationships between birthweight (BW), weight gain and BP later in life remain uncertain. We examined the effects of early life growth on BP among Ugandan adolescents. METHODS: Data were collected prenatally from women and their offspring were followed from birth, with BP measured following standard protocols in early adolescence. Weight-for-age Z-scores (WAZ) were computed using World Health Organization references. Linear regression was used to relate BW, and changes in WAZ between birth and 5 years, to adolescents' BP, adjusting for confounders. RESULTS: Among 2345 live offspring, BP was measured in 1119 (47.7%) adolescents, with mean systolic BP 105.9 mmHg and mean diastolic BP 65.2 mmHg. There was little evidence of association between BW and systolic [regression coefficient β = 0.14, 95% confidence interval (CI) (-1.00, 1.27)] or diastolic [β = 0.43, 95% CI (-0.57, 1.43)] BP. Accelerated weight gain between birth and 5 years was associated with increased BP: systolic β = 1.17, 95% CI (0.69, 1.66) and diastolic β = 1.03, 95% CI (0.59, 1.47). Between birth and 6 months of age, effects of accelerated weight gain on adolescent BP were strongest among the LBW (both premature and small-for-gestational-age) children [BW < 2.5 kg: β = 2.64, 95% CI (0.91, 4.37), BW≥2.5 kg: β = 0.58, 95% CI (0.01, 1.14), interaction P-value =  0.024]. CONCLUSIONS: Findings from this large tropical birth cohort in Uganda suggest that postnatal weight gain rather than BW is important in the developmental programming of BP, with fast-growing LBW children at particular risk. Efforts to control BP should adopt a life course approach

The determinants of lipid profiles in early adolescence in a Ugandan birth cohort

Dyslipidaemia in adolescence tracks into adulthood and is an important risk factor for cardiovascular disease. Little is known about the effects of environmental exposures and early-life exposure to infectious diseases common to tropical regions on lipids. In 1119 early adolescent participants in the Entebbe Mother and Baby Study, we used linear regression to examine whether prenatal, childhood or adolescent factors are associated with lipid levels. Reduced high-density lipoprotein (HDL) and elevated triglyceride levels were common (prevalence 31% and 14%, respectively), but elevated low-density lipoprotein (LDL) or total cholesterol (TC) were rare. Current malaria infection was associated with lower mean LDL (adjusted ß - 0.51; 95% CI - 0.81, - 0.21), HDL (adjusted ß - 0.40; 95% CI - 0.56, - 0.23), and TC levels (adjusted ß - 0.62; 95% CI - 0.97, - 0.27), but higher mean triglyceride levels (geometric mean ratio (GMR) 1.47; 95% CI 1.18-1.84). Early-life asymptomatic malaria was associated with modest reductions in HDL and TC. Body mass index (BMI) was positively associated with LDL, TC, and triglycerides. No associations with helminth infection were found. Our findings suggest that early-life factors have only marginal effects on the lipid profile. Current malaria infection and BMI are strongly associated with lipids and important to consider when trying to improve the lipid profile

Blood pressure risk factors in early adolescents: results from a Ugandan birth cohort.

We aimed to investigate life-course factors associated with blood pressure (BP) among Ugandan adolescents. Between 9th April 2003 and 24th November 2005, 2507 pregnant women from Entebbe municipality and Katabi sub-county were enrolled into a deworming trial. The resulting 2345 live-born offspring were followed to age 10 or 11 years, when between 20th May 2014 to 16th June 2016, BP was measured following standard protocols. Factors associated with BP were assessed using multivariable linear regression. BP was measured in 1119 adolescents with a median age of 10.2 years. Mean systolic BP and diastolic BP was 105.9 mmHg (standard deviation (SD) 8.2) and 65.2 mmHg (SD 7.3), respectively. Maternal gestational body mass index (BMI), higher maternal education status and family history of hypertension were positively associated with adolescent BP. Childhood (age ≤5 years) malaria was associated with lower adolescent systolic BP. Factors measured at time of BP measurement positively associated with systolic BP were age, BMI, waist circumference and Trichuris trichiura (whipworm) infection; higher vegetable consumption was associated with lower systolic BP. Results for diastolic BP were similar, except higher fruit, rather than higher vegetable consumption was associated with lower diastolic BP and there was no association with waist circumference or Trichuris trichiura infection. In summary, life-course exposures were associated with adolescent BP in this tropical birth cohort. Malaria early in life could impact later BP. Interventions initiated early in life targeting individuals with family history of hypertension, aiming to reduce adiposity (in pregnancy and adolescence) and promoting fruit and vegetable consumption might contribute to reducing the risk of high BP and subsequent cardiovascular diseases

The Impact of Intensive Versus Standard Anthelminthic Treatment on Allergy-related Outcomes, Helminth Infection Intensity, and Helminth-related Morbidity in Lake Victoria Fishing Communities, Uganda: Results From the LaVIISWA Cluster-randomized Trial.

BACKGROUND: The prevalence of allergy-related diseases is increasing in low-income countries. Parasitic helminths, common in these settings, may be protective. We hypothesized that intensive, community-wide, anthelminthic mass drug administration (MDA) would increase allergy-related diseases, while reducing helminth-related morbidity. METHODS: In an open, cluster-randomized trial (ISRCTN47196031), we randomized 26 high-schistosomiasis-transmission fishing villages in Lake Victoria, Uganda, in a 1:1 ratio to receive community-wide intensive (quarterly single-dose praziquantel plus albendazole daily for 3 days) or standard (annual praziquantel plus 6 monthly single-dose albendazole) MDA. Primary outcomes were recent wheezing, skin prick test positivity (SPT), and allergen-specific immunoglobulin E (asIgE) after 3 years of intervention. Secondary outcomes included helminths, haemoglobin, and hepatosplenomegaly. RESULTS: The outcome survey comprised 3350 individuals. Intensive MDA had no effect on wheezing (risk ratio [RR] 1.11, 95% confidence interval [CI] 0.64-1.93), SPT (RR 1.10, 95% CI 0.85-1.42), or asIgE (RR 0.96, 95% CI 0.82-1.12). Intensive MDA reduced Schistosoma mansoni infection intensity: the prevalence from Kato Katz examinations of single stool samples from each patient was 23% versus 39% (RR 0.70, 95% CI 0.55-0.88), but the urine circulating cathodic antigen test remained positive in 85% participants in both trial arms. Hookworm prevalence was 8% versus 11% (RR 0.55, 95% CI 0.31-1.00). There were no differences in anemia or hepatospenomegaly between trial arms. CONCLUSIONS: Despite reductions in S. mansoni intensity and hookworm prevalence, intensive MDA had no effect on atopy, allergy-related diseases, or helminth-related pathology. This could be due to sustained low-intensity infections; thus, a causal link between helminths and allergy outcomes cannot be discounted. Intensive community-based MDA has a limited impact in high-schistosomiasis-transmission fishing communities, in the absence of other interventions. CLINICAL TRIALS REGISTRATION: ISRCTN47196031

The Effect of Helminth Infections and Their Treatment on Metabolic Outcomes: Results of a Cluster-Randomized Trial.

BACKGROUND: Helminths may protect against cardiometabolic risk through effects on inflammation and metabolism; their treatment may be detrimental to metabolic outcomes. METHODS: In a cluster-randomized trial in 26 Ugandan fishing communities we investigated effects of community-wide intensive (quarterly single-dose praziquantel, triple-dose albendazole) vs standard (annual single-dose praziquantel, biannual single-dose albendazole) anthelminthic treatment on metabolic outcomes, and observational associations between helminths and metabolic outcomes. The primary outcome, homeostatic model assessment of insulin resistance (HOMA-IR), and secondary outcomes (including blood pressure, fasting blood glucose, lipids) were assessed after 4 years' intervention among individuals aged ≥10 years. RESULTS: We analyzed 1898 participants. Intensive treatment had no effect on HOMA-IR (adjusted geometric mean ratio, 0.96 [95% confidence interval {CI}, .86-1.07]; P = .42) but resulted in higher mean low-density lipoprotein cholesterol (LDL-c) (2.86 vs 2.60 mmol/L; adjusted mean difference, 0.26 [95% CI, -.03 to .56]; P = .08). Lower LDL-c levels were associated with Schistosoma mansoni (2.37 vs 2.80 mmol/L; -0.25 [95% CI, -.49 to -.02]; P = .04) or Strongyloides (2.34 vs 2.69 mmol/L; -0.32 [95% CI, -.53 to -.12]; P = .003) infection. Schistosoma mansoni was associated with lower total cholesterol (4.24 vs 4.64 mmol/L; -0.25 [95% CI, -.44 to -.07]; P = .01) and moderate to heavy S. mansoni infection with lower triglycerides, LDL-c, and diastolic blood pressure. CONCLUSIONS: Helminth infections improve lipid profiles and may lower blood pressure. Studies to confirm causality and investigate mechanisms may contribute to understanding the epidemiological transition and suggest new approaches to prevent cardiometabolic disease. CLINICAL TRIALS REGISTRATION: ISRCTN47196031

Population differences in vaccine responses (POPVAC): scientific rationale and cross-cutting analyses for three linked, randomised controlled trials assessing the role, reversibility and mediators of immunomodulation by chronic infections in the tropics.

INTRODUCTION: Vaccine-specific immune responses vary between populations and are often impaired in low income, rural settings. Drivers of these differences are not fully elucidated, hampering identification of strategies for optimising vaccine effectiveness. We hypothesise that urban-rural (and regional and international) differences in vaccine responses are mediated to an important extent by differential exposure to chronic infections, particularly parasitic infections. METHODS AND ANALYSIS: Three related trials sharing core elements of study design and procedures (allowing comparison of outcomes across the trials) will test the effects of (1) individually randomised intervention against schistosomiasis (trial A) and malaria (trial B), and (2) Bacillus Calmette-Guérin (BCG) revaccination (trial C), on a common set of vaccine responses. We will enrol adolescents from Ugandan schools in rural high-schistosomiasis (trial A) and rural high-malaria (trial B) settings and from an established urban birth cohort (trial C). All participants will receive BCG on day '0'; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. Primary outcomes are BCG-specific IFN-γ responses (8 weeks after BCG) and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine effects of interventions on correlates of protective immunity, vaccine response waning, priming versus boosting immunisations, and parasite infection status and intensity. Overarching analyses will compare outcomes between the three trial settings. Sample archives will offer opportunities for exploratory evaluation of the role of immunological and 'trans-kingdom' mediators in parasite modulation of vaccine-specific responses. ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications. TRIAL REGISTRATION NUMBERS: ISRCTN60517191, ISRCTN62041885, ISRCTN10482904