Community cohort study of rotavirus and other enteropathogens: are routine vaccinations associated with sex-differential incidence rates?

OBJECTIVE: Community studies in West Africa have demonstrated that routine vaccinations may have non-targeted effects, the female-male mortality ratio being reduced after administration of BCG and increased after diphtheria-tetanus-pertussis (DTP). We examined whether immunisation status was associated with infection with rotavirus and other enteropathogens. METHODS: We recruited 200 children shortly after birth and followed them until 2 years of age with weekly morbidity interviews and stool sampling. Vaccination status for each child was classified according to the most recent vaccination as documented by vaccination card. MAIN OUTCOME MEASURES: The female-male incidence rate ratios (IRR) of infection with an enteropathogen and of enteropathogen-associated diarrhoea were estimated for children according to whether they had received BCG or DTP as their last vaccination. RESULTS: For children who received BCG as their last vaccine, the adjusted female-male IRRs for primary rotavirus-infection and diarrhoea were 1.05 (95% CI: 0.21-5.28) and 0.0 (95% CI: 0-3.02), respectively. For children who received DTP as their last vaccine, the adjusted female-male IRRs were 1.93 (0.89-4.21) and 1.92 (0.70-5.32), respectively, for rotavirus-associated infection and diarrhoea. Restricted to the rotavirus season, the female-male IRRs for rotavirus infection and diarrhoea were 2.56 (1.17-5.63) and 2.63 (0.94-7.34), respectively. The female-male IRR for rotavirus-associated diarrhoea differed significantly among BCG and DTP recipients (p=0.02). Infections with enteropathogens not associated with diarrhoea were associated with lower female-male IRRs after BCG of 0.82 (0.55-1.23) and higher female-male IRRs after DTP vaccination of 1.32 (1.03-1.70) for primary infection (p=0.05). Though there were few infections with other diarrhoea-causing enteropathogens, these were also associated with a lower female-male IRR after BCG of 0.62 (0.26-1.52) and a higher female-male IRR after DTP vaccination of 1.51 (1.04-2.20) for all infection. CONCLUSION: Routine immunisations may affect morbidity for non-targeted infections. As in studies of infant mortality, BCG is associated with lower risk for girls, whereas, DTP is associated with higher risk for girls relative to boys.     

From current vaccine recommendations to everyday practices: An analysis in five sub-Saharan African countries

BackgroundEstimates of WHO and UNICEF vaccination coverage may provide little insight into the extent to which vaccinations are administered on time. Yet, lack of adherence to the recommended age to receive a specific vaccination may have detrimental health consequences. For example, delays in receiving vaccination will prolong the risk of lack of protection, often when disease risk is highest, such as during early infancy. We estimated the reported age at vaccination, and vaccine coverage at different ages in children from five sub-Saharan African countries.MethodsWe analyzed data from the latest Demographic and Health Programme databases available for Burkina Faso 2010 (n = 15,044 observations), Ghana 2008 (n = 2992), Kenya 2008–9 (n = 6079), Senegal 2010–11 (n = 12,326), and Tanzania 2010 (n = 8023). We assessed, amongst vaccinees, the exact age when vaccine was administered for the three infant doses of pentavalent vaccine (DTP) and the first dose of measles-containing-vaccine (MCV), as well as the proportion of children immunized with these antigens by a certain age. Vitamin A supplementation (VAS) coverage was evaluated as a potential contact visit for vaccine introduction.ResultsFor all DTP doses, the median intervals between recommended and actual ages of receiving vaccination ranged from 12, 17 and 23 days in Kenya, to 22, 33 and 45 days in Senegal. MCV was mostly given during the recommended age of 9 months. In each country, there was a large discrepancy in the median age at DTP vaccination between regions. VAS coverage in young children ranged from 30.3% in Kenya to 78.4% in Senegal, with large variations observed between areas within each study country.ConclusionIn the context of new vaccine introduction, age of children at vaccination should be monitored to interpret data on vaccine-preventable disease burden, vaccine effectiveness, and vaccine safety, and to adapt targeted interventions and messages.     

Safety of maternal pertussis vaccination on pregnancy and birth outcomes: A prospective cohort study

ObjectiveTo evaluate the safety of maternal pertussis vaccination on pregnancy and birth outcomes.MethodsThe study population comprised 1272 healthy nulliparous pregnant women who participated in Screening Tests to identify poor Outcomes in Pregnancy (STOP) study at two obstetric hospitals in South Australia between 2015 and 2018. Participants were followed prospectively, with vaccination (confirmed by medical records), extensive amounts of pregnancy and birth outcome data collected by research midwives. Adjusted relative risks (aRRs) and hazard ratios (aHRs) were estimated accounting for time-varying vaccine exposure and the temporal nature of each outcome.ResultsOf the 1272 women included in this study, 80.1% (n = 1019) received maternal pertussis vaccination. Vaccinated women had an average 0.22 weeks (95% CI 0.001, 0.44) longer gestation at delivery compared to unvaccinated women. Maternal pertussis vaccination was not associated with chorioamnionitis (aRR 0.71, 95% CI 0.27,1.82), gestational hypertension (aHR 1.24, 95% CI, 0.66, 2.30), preeclampsia (aHR 0.75, 95% CI 0.47, 1.18) nor preterm birth (aHR 0.99, 95% CI 0.47, 2.07). Neither risk of low birth weight (aHR 0.72, 95% CI 0.41, 1.27) nor small for gestational age infants (aHR 0.67,95% CI 0.29, 1.55) were increased following maternal pertussis vaccination. No associations between pertussis vaccination during pregnancy and adverse birth outcomes including admission to the neonatal care unit, low Apgar scores, and mechanical ventilation were observed. Results were not materially changed after adjustment for maternal influenza vaccination.ConclusionOur study provides reassuring evidence of the safety of maternal pertussis vaccination with no increased risk of adverse pregnancy and birth outcomes. These findings support recommendations for pertussis vaccination during pregnancy to prevent morbidity and mortality associated with early-infant pertussis disease.     

Longitudinal,population-based cohort study of prenatal influenza vaccination and influenza infection in childhood

BackgroundInfluenza vaccination is recommended to protect mothers and their infants from influenza infection. Few studies have evaluated the health impacts of in utero exposure to influenza vaccine among children more than six months of age.MethodsWe used probabilistically linked administrative health records to establish a mother–child cohort to evaluate the risk of influenza and acute respiratory infections associated with maternal influenza vaccination. Outcomes were laboratory-confirmed influenza (LCI) and hospitalization for influenza or acute respiratory infection (ARI). Adjusted hazard ratios (aHRs) accounted for child’s Aboriginal status and were weighted by the inverse-probability of treatment.Results14,396 (11.5%) children were born to vaccinated mothers. Maternally vaccinated infants aged < 6 months had lower risk of LCI (aHR: 0.33; 95% CI: 0.13, 0.85), influenza-associated hospitalization (aHR: 0.39; 95% CI: 0.16, 0.94) and ARI-associated hospitalization (aHR: 0.85; 95% CI: 0.77, 0.94) compared to maternally unvaccinated infants. With the exception of an increased risk of LCI among children aged 6 months to < 2 years old following first trimester vaccination (aHR: 2.28; 95% CI: 1.41, 3.69), there were no other differences in the risk of LCI, influenza-associated hospitalization or ARI-associated hospitalization among children aged > 6 months.ConclusionStudy results show that maternal influenza vaccination is effective in preventing influenza in the first six months and had no impact on respiratory infections after two years of age.     

Does BCG provide long-term protection against SARS-CoV-2 infection? A case–control study in Quebec,Canada

BackgroundEarly in the coronavirus disease 2019 (COVID-19) pandemic, before severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines became available, it was hypothesized that BCG (Bacillus Calmette–Guérin), which stimulates innate immunity, could provide protection against SARS-CoV-2. Numerous ecological studies, plagued by methodological deficiencies, revealed a country-level association between BCG use and lower COVID-19 incidence and mortality. We aimed to determine whether BCG administered in early life decreased the risk of SARS-CoV-2 infection in adulthood and the severity of COVID-19.MethodsThis case-control study was conducted in Quebec, Canada. Cases were patients with a positive SARS-CoV-2 nucleic acid amplification test performed at two hospitals between March–October 2020. Controls were identified among patients with non-COVID-19 samples processed by the same microbiology laboratories during the same period. Enrolment was limited to individuals born in Quebec between 1956 and 1976, whose vaccine status was accessible in a computerized registry of 4.2 million BCG vaccinations.ResultsWe recruited 920 cases and 2123 controls. Fifty-four percent of cases (n = 424) and 53% of controls (n = 1127) had received BCG during childhood (OR: 1.03; 95% CI: 0.89–1.21), while 12% of cases (n = 114) and 11% of controls (n = 235) had received two or more BCG doses (OR: 1.14; 95% CI: 0.88–1.46). After adjusting for age, sex, material deprivation, recruiting hospital and occupation there was no evidence of protection conferred by BCG against SARS-CoV-2 (AOR: 1.01; 95% CI: 0.84–1.21). Among cases, 77 (8.4%) needed hospitalization and 18 (2.0%) died. The vaccinated were as likely as the unvaccinated to require hospitalization (AOR: 1.01, 95% CI: 0.62–1.67) or to die (AOR: 0.85, 95% CI: 0.32–2.39).ConclusionsBCG does not provide long-term protection against symptomatic COVID-19 or severe forms of the disease.     

The impact of a change in infant BCG vaccination policy on adolescent TB incidence rates: A South African population-level cohort study

ObjectiveSouth Africa’s infant Bacille Calmette Guerin (BCG) vaccine policy changed from percutaneous (PC) BCG Japan to intradermal (ID) BCG Denmark in 2000. This study investigated whether this change in infant BCG vaccination had any durable impact on TB incidence rates (IR) into adolescence.MethodsThe Cape Town electronic TB register provided data (from 2008 to 2018) on HIV-negative TB patients born in 1991–1999 (BCG Japan cohort) and 2001–2008 (BCG Denmark cohort). Statistics South Africa provided population estimates. Annual TB IR per 100,000 population were calculated stratified by age, gender and birth year. Interrupted time series analysis with a segmented Poisson regression and birth cohort analyses were used to compare incidence between the BCG cohorts and trends over time.FindingsTB IR increased throughout adolescence, with 17-year-olds having 7.34 [95% confidence interval (CI), 6.48–8.32] times higher TB IR than 10-year-olds. Females had 1.22 [95% CI 1.17–1.27] higher IR than males. Overall, adolescents who received ID BCG Denmark had a lower TB IR compared to PC BCG Japan (rate ratio 0.86, [95% CI 0.80–0.94]). No interaction between BCG and age, nor BCG and gender were identified. Birth cohort analyses showed the increase in TB IR started around one year earlier in females than in males.ConclusionThe change in infant BCG policy was associated with a modest decrease in TB incidence in 10- to 17-year-old HIV-negative adolescents. However, TB incidence rapidly increased with age in both adolescent cohorts and remained high despite BCG vaccination at birth.     

Community cohort study of Cryptosporidium parvum infections: sex-differential incidences associated with BCG and diphtheria-tetanus-pertussis vaccinations

OBJECTIVE: Community studies in West Africa have suggested that routine vaccinations may have sex-differential non-targeted effects, the female-male mortality ratios being increased after receiving diphtheria-tetanus-pertussis (DTP) vaccination and reduced after administration of BCG or measles vaccine (MV). Using an existing data set, we examined whether vaccinations were associated with gender-differential incidences of Cryptosporidium parvum infection. METHODS: Two hundred children had been recruited shortly after birth and followed until 2 years of age or until follow-up was interrupted by a war. We performed weekly morbidity interviews and collected stool specimens, irrespective of whether the children had diarrhoea. Vaccination status for each child was classified according to the most recent vaccination with BCG, DTP, or MV. FINDINGS: The female-male incidence rate ratio (IRR) for Cryptosporidium infection among children who had received BCG as their last vaccine was 0.0 (95% CI: 0-3.49). However, among those who had received DTP as their last vaccine, the female-male IRR was 6.25 (2.06-18.9) for Cryptosporidium infection and 3.60 (0.91-14.2) for Cryptosporidium-associated diarrhoea. The female-male IRRs for Cryptosporidium infection differed significantly among BCG and DTP recipients (p=0.01). Among children who had received measles as their last routine vaccine, the female-male IRR was 1.57 (0.60-4.11) for Cryptosporidium infection and 0.98 (0.28-3.52) for Cryptosporidium-associated diarrhoea. The female-male IRRs for Cryptosporidium infection differed among DTP and MV recipients (p=0.02). For girls, early DTP vaccination compared with late or no DTP vaccination was associated with increased incidence rate of Cryptosporidium infection (IRR=4.23 (1.04-17.2)). For girls, the incidence rate decreased when they received MV. INTERPRETATION: Routine immunisations may affect morbidity for non-targeted infections. As in studies of infant mortality, BCG is associated with a low risk for girls relative to boys, whereas DTP is associated with a high female-male IRR of C. parvum infection.     

Cost-effectiveness of maternal pertussis immunization: Implications of a dynamic transmission model for low- and middle-income countries

ObjectiveThis study evaluates the cost-effectiveness of maternal acellular pertussis (aP) immunization in low- and middle-income countries using a dynamic transmission model.MethodsWe developed a dynamic transmission model to simulate the impact of infant vaccination with whole-cell pertussis (wP) vaccine with and without maternal aP immunization. The model was calibrated to Brazilian surveillance data and then used to project health outcomes and costs under alternative strategies in Brazil, and, after adjusting model parameter values to reflect their conditions, in Nigeria and Bangladesh. The primary measure of cost-effectiveness is incremental cost (2014 USD) per disability-adjusted life-year (DALY).ResultsThe dynamic model shows that maternal aP immunization would be cost-effective in Brazil, a middle-income country, under the base-case assumptions, but would be very expensive at infant vaccination coverage in and above the threshold range necessary to eliminate the disease (90–95%). At 2007 infant coverage (DTP1 90%, DTP3 61% at 1 year of age), maternal immunization would cost < $4,000 per DALY averted. At high infant coverage, such as Brazil in 1996 (DTP1 94%, DTP3 74% at 1 year), cost/DALY increases to $1.27 million. When the model’s time horizon was extended from 2030 to 2100, cost/DALY increased under both infant coverage levels, but more steeply with high coverage. The results were moderately sensitive to discount rate, maternal vaccine price, and maternal aP coverage and were robust using the 100 best-fitting parameter sets. Scenarios representing low-income countries showed that maternal aP immunization could be cost-saving in countries with low infant coverage, such as Nigeria, but very expensive in countries, such as Bangladesh, with high infant coverage.ConclusionA dynamic model, which captures the herd immunity benefits of pertussis vaccination, shows that, in low- and middle-income countries, maternal aP immunization is cost-effective when infant vaccination coverage is moderate, even cost-saving when it is low, but not cost-effective when coverage levels pass 90–95%.     

Retesting the hypothesis that early Diphtheria-Tetanus-Pertussis vaccination increases female mortality: An observational study within a randomised trial

BackgroundThere are worrying indications that diphtheria-tetanus-pertussis (DTP) vaccine has negative non-specific effects for females. We previously found, in a trial of early-Bacillus Calmette-Guérin (BCG) to low weight (LW) neonates, that receiving early-DTP (before 2 months of age), was associated with increased female mortality compared with no-DTP/delayed-DTP. Within a subsequent LW trial, we aimed to retest this observation.MethodsBetween 2010 and 2014, in Guinea-Bissau, 2,398 infants were randomised 1:1 to early-BCG (intervention) or delayed-BCG (standard practice for LW neonates) and visited at 2, 6 and 12 months of age to assess nutritional and vaccination status. DTP is recommended at 6 weeks of age. We examined the effect of having “early-DTP” versus “no-DTP” at the time of the 2-month visit on all-cause mortality between the 2- and 6-month visits in Cox models stratified by sex and adjusted for BCG-group and 2-month-weight-for-age (z-scores) providing adjusted mortality rate ratios (aMRRs). We analysed to which extent conditions varied between the present and the previous LW trials and how that might have affected the overall result of comparing the early-DTP and the no-DTP groups.ResultsAt the time of the 2-month visit, 75% (1,795/2,398) had received DTP. Those vaccinated had better anthropometric indices than no-DTP infants at birth and by 2 months of age. Between the 2- and 6-month visits, 29 deaths occurred. The early-DTP/no-DTP aMRR was 1.09 (95% CI: 0.44–2.69); 1.19 (0.45–3.15) for females and 0.77 (0.14–4.19) for males. Compared to the previous study, the present study cohort had 56% (30–72%) lower overall mortality, fewer no-DTP infants, higher BCG vaccination coverage and several more oral polio vaccine campaigns.ConclusionWe did not find that early-DTP was associated with increased female mortality as found in a previous study; differences in results may partly be due to a decline in overall mortality and changes in vaccination practices.     

The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study

BACKGROUND: and objective Previous studies from areas with high mortality in West Africa have not found diphtheria-tetanus-pertussis (DTP) vaccine to be associated with the expected reduction in mortality, a few studies suggesting increased mortality. We therefore examined mortality when DTP was first introduced in rural areas of Guinea-Bissau in 1984-1987. Setting Twenty villages in four regions have been followed with bi-annual examinations since 1979. SUBJECTS: In all, 1657 children aged 2-8 months. Design Children were weighed when attending the bi-annual examinations and they were vaccinated whenever vaccines were available. DTP was introduced in the beginning of 1984, oral polio vaccine later that year. We examined mortality for children aged 2-8 months who had received DTP and compared them with children who had not been vaccinated because they were absent, vaccines were not available, or they were sick. MAIN OUTCOME MEASURE: Mortality over the next 6 months from the day of examination for vaccinated and unvaccinated children. RESULTS: Prior to the introduction of vaccines, children who were absent at a village examination had the same mortality as children who were present. During 1984-1987, children receiving DTP at 2-8 months of age had higher mortality over the next 6 months, the mortality rate ratio (MR) being 1.92 (95% CI: 1.04, 3.52) compared with DTP-unvaccinated children, adjusting for age, sex, season, period, BCG, and region. The MR was 1.81 (95% CI: 0.95, 3.45) for the first dose of DTP and 4.36 (95% CI: 1.28, 14.9) for the second and third dose. BCG was associated with slightly lower mortality (MR = 0.63, 95% CI: 0.30, 1.33), the MR for DTP and BCG being significantly inversed. Following subsequent visits and further vaccinations with DTP and measles vaccine, there was no difference in vaccination coverage and subsequent mortality between the DTP-vaccinated group and the initially DTP-unvaccinated group (MR = 1.06, 95% CI: 0.78, 1.44). CONCLUSIONS: In low-income countries with high mortality, DTP as the last vaccine received may be associated with slightly increased mortality. Since the pattern was inversed for BCG, the effect is unlikely to be due to higher-risk children having received vaccination. The role of DTP in high mortality areas needs to be clarified.     

Seasonal influenza vaccination is associated with reduced risk of death among Medicare beneficiaries☆

BackgroundInfluenza causes substantial mortality, especially among older persons. Influenza vaccines are rarely more than 50% effective and rarely reach more than half of the US Medicare population, which is primarily an aged population. We wished to estimate the association between vaccination and mortality reduction.MethodWe used the US Center for Medicare and Medicaid Services (CMS) DataLink Project to determine vaccination status and timing during the 2017–2018 influenza season for more than 26 million Medicare enrollees. Patient-level demographic, health, co-morbidity, hospitalization, vaccination, and healthcare utilization claims data were supplied as covariates to general linear models in order to isolate and estimate the association between participation in the vaccination program and relative risk of death.FindingsThe 2017–2018 seasonal influenza vaccine reduced (Relative Risk Ratio [RRR] 0.936 [95% CI = 0.918–0.954]) the risk of all-cause death among beneficiaries following a hospitalization for sepsis and moreover the risk of death without a prior hospitalization during the 2.5-month outcome window (RRR 0.870 [95% CI = 0.853–0.887]). We estimate the number needed to vaccinate (NNV) to prevent a death in the ten-week outcome window is between 1,515 beneficiaries (95% CI = 1,351–1,754; derived from the average treatment effect of augmented inverse probability weighting) and 1,960 beneficiaries (95% CI = 1,695–2,381; derived from the average marginal effect of logistic regression). Among beneficiaries requiring hospitalization, the greatest death risk reduction accrued to those 85 + years of age who were hospitalized with sepsis, RRR 0.92 [95% CI = 0.89–0.95]. No apparent benefit was realized by beneficiaries who required custodial (nursing home) care.InterpretationSeasonal influenza immunization is associated with relative reduction of death risk among non-institutionalized Medicare beneficiaries.FundingAll authors are full-time or contractual employees of the United States Federal Government, Department of Health and Human Services, the funding agency.     

Different effects of BCG strains – A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau

BackgroundDifferent Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau.MethodsDuring 2011–2013, infants in the Bandim Health Project’s urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45 days in Cox proportional hazards models. Scar prevalence and size were compared using binomial regression and ranksum tests.ResultsAmong 1206 children, 18% received Danish BCG (n = 215) and 82% Russian BCG (n = 991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60–1.46) for Danish BCG compared with Russian BCG. Girls vaccinated with Danish BCG tended to have lower consultation rates compared with girls vaccinated with Russian BCG (aHR 0.56 (0.25–1.24)), whereas the effect was opposite for boys (aHR 1.24 (0.74–2.11)), p = 0.09. Children vaccinated with Danish BCG were more likely to develop a scar (97%) than children vaccinated with Russian BCG (87%), the relative risk (RR) being 1.11 (1.06–1.16). The effect was stronger in girls, and BCG scar size was larger among infants vaccinated with the Danish strain.ConclusionBCG strain influences scar prevalence and scar size, and may have sex differential effects on morbidity. BCG strains are currently used interchangeably, but BCG scarring has been linked to subsequent survival. Hence, more research into the health effects of different BCG strains is warranted. Small adjustments of BCG production could potentially lower childhood morbidity and mortality at low cost.     

Smallpox and BCG vaccination in childhood and cutaneous malignant melanoma in Danish adults followed from 18 to 49 years

BackgroundEarly smallpox and Bacillus Calmette-Guérin (BCG) vaccinations have been associated with reduced risk of cutaneous malignant melanoma (CMM). We assessed the association between pre-school smallpox vaccination and early-school BCG vaccination and CMM in a young Danish population.MethodsWe conducted a register-based case-cohort study of individuals growing up during the phase-out period of smallpox and BCG vaccination in Denmark (born 1965–1976) utilising the decrease in vaccination during this period. Information on childhood vaccinations and potential confounders from Copenhagen school health records were linked with nationwide registers on cancer (CMM diagnoses), migrations and deaths by personal identification numbers.ResultsThe individuals were followed from age 18 until 31/12/2014 (maximum age at end of follow-up, 49 years). 188 cases of CMM occurred in the background population of 46,239 individuals; 172 CMM cases (91%) had full information and were analysed. The adjusted hazard ratio (HR) for CMM by BCG and/or smallpox vaccination compared with neither vaccine was 1.29 (95% confidence interval (CI) 0.72–2.31). For smallpox vaccination only, HR = 1.23 (95% CI 0.53–2.86) for BCG vaccination only, HR = 1.13 (95% CI 0.61–2.09) and for both smallpox and BCG vaccination, HR = 1.75 (95% CI 0.87–3.48) compared with none of these. Vaccination below the age of one year gave similar results.ConclusionsWe found no strong beneficial effect of smallpox and BCG vaccination against CMM among young adult Danes and with broad confidence intervals our data alone could be compatible with both modest preventive effects, no effects, and modest harmful effects. Our estimates do not contradict a potential modest beneficial effect of neonatal vaccination.     

Validity of the estimates of oral cholera vaccine effectiveness derived from the test-negative design

BackgroundThe test-negative design (TND) has emerged as a simple method for evaluating vaccine effectiveness (VE). Its utility for evaluating oral cholera vaccine (OCV) effectiveness is unknown. We examined this method's validity in assessing OCV effectiveness by comparing the results of TND analyses with those of conventional cohort analyses.MethodsRandomized controlled trials of OCV were conducted in Matlab (Bangladesh) and Kolkata (India), and an observational cohort design was used in Zanzibar (Tanzania). For all three studies, VE using the TND was estimated from the odds ratio (OR) relating vaccination status to fecal test status (Vibrio cholerae O1 positive or negative) among diarrheal patients enrolled during surveillance (VE =  (1 − OR)×100%). In cohort analyses of these studies, we employed the Cox proportional hazard model for estimating VE (=1 − hazard ratio)×100%).ResultsOCV effectiveness estimates obtained using the TND (Matlab: 51%, 95% CI:37–62%; Kolkata: 67%, 95% CI:57–75%) were similar to the cohort analyses of these RCTs (Matlab: 52%, 95% CI:43–60% and Kolkata: 66%, 95% CI:55–74%). The TND VE estimate for the Zanzibar data was 94% (95% CI:84–98%) compared with 82% (95% CI:58–93%) in the cohort analysis. After adjusting for residual confounding in the cohort analysis of the Zanzibar study, using a bias indicator condition, we observed almost no difference in the two estimates.ConclusionOur findings suggest that the TND is a valid approach for evaluating OCV effectiveness in routine vaccination programs.     

Vaccine safety in HIV-infected adults within the Vaccine Safety Datalink Project

ObjectivesWe evaluate safety of routine vaccination among adults infected with human immunodeficiency virus (HIV) in five healthcare organizations in the United States.MethodsWe conducted a retrospective cohort study of HIV-infected adults who received inactivated influenza vaccines, hepatitis B vaccines, pneumococcal vaccines, or tetanus, diphtheria, and acellular pertussis vaccines between 2002 and 2013. We conducted self-controlled case series analysis to estimate the relative risk (RR) for 11 pre-specified adverse events (AEs) requiring medical attention.ResultsAmong 20,417 HIV-infected adults (90.2% male), a total of 137,674 vaccine doses were administered. Based on ICD-9 codes, we detected an increased risk of cellulitis and infection (RR: 1.18, 95% CI: 1.03–1.35) among all patients, and an increased risk of stroke/cerebrovascular diseases among patients with an HIV viral load >10,000 copies/ml (adjusted RR: 3.94, 95% CI: 1.32–11.72). Further analyses on chart confirmed cases of stroke/cerebrovascular diseases indicated no statistically significant increased risk (adjusted RR: 1.72, 95% CI: 0.41–7.24). There was no evidence of increased risk for other AEs following routine vaccination in HIV-infected adults.ConclusionsRoutinely administered vaccines are generally safe for HIV-infected adults.     

The effect of exercise on vaccine-related pain,anxiety and fear during HPV vaccinations in adolescents

IntroductionWith increased school-based vaccinations for improved coverage rates and practicality, the World Health Organization (WHO) recently endorsed research to identify possible interventions to reduce vaccine-related pain in mass clinical and school-based settings. In particular, the lack of research in adolescents indicate a particular need in this population. Acute exercise has analgesic effects and has been used as a behavioural adjuvant to vaccination. Here, we examine the effect of exercise on vaccine-related pain, anxiety and fear in adolescents, during a school-based program for HPV vaccinations.Methods116 students (Female: 61, Male: 55) aged 11–13 years were randomly allocated to either an Exercise (n = 60) or Control (n = 56) group. All participants completed demographic and Trait-anxiety questionnaires prior to receiving the vaccine according to usual care. The Exercise group also performed upper body exercise for 15 min prior to receiving the vaccine. Immediately after the vaccine administration, all participants reported on pain, anxiety and fear at the time of receiving the vaccine.ResultsFemale adolescents in the Exercise group reported significantly less pain (3.64; 95% CI, 2.98–4.30) than Controls (4.58; 95% CI, 3.96–5.19; p = 0.04). Further, females reported greater pain and anxiety than males in the Control group but not the Exercise group.ConclusionThis study supports the use of exercise prior to vaccine administration, especially in female adolescents who are particularly vulnerable to negative experiences during vaccination procedures. Furthermore, the ease of application, as well as the benefit of exercise, provides support for the use of simple exercise prior to vaccination in mass vaccination settings.Clinical trial registry: ANZCTR, ACTRN12614001185651.     

Fewer out-of-sequence vaccinations and reduction of child mortality in Northern Ghana

BackgroundStudies suggest that diphtheria-tetanus-pertussis (DTP) vaccine administered simultaneously with measles vaccine (MV) or DTP administered after MV are associated with higher child mortality than having MV-after-DTP3 as most recent vaccination. We tested this in Northern Ghana where the prevalence of such out-of-sequence vaccinations has declined.MethodsUsing annual cohort data of children aged 12–23 months from 1996 to 2012 and Cox proportional hazards models, we assessed survival in relation to the most recent vaccination status within the next 12 months and until five years of age. We assessed whether mortality in children aged 12–59 months was higher when the most recent vaccine was non-live (DTP) rather than live (MV or OPV).ResultsOut-of-sequence vaccinations with DTP-containing vaccines and MV declined from 86% in 1989 to 24% in 1996 and 0.7% in 2012. Between 1996 and 2012, 38 070 children had their vaccinations status assessed: the adjusted hazard ratio (HR) for out-of-sequence vaccinations (DTP >= MV) compared with the recommended sequence of MV-after-DTP3 was 1.42(1.06–1.90) during the first 12 months after assessment of vaccination status and 1.29(1.03–1.60) with follow-up to five years of age; the HR was 2.58(1.14–5.84) before OPV or MV campaigns and 1.37(1.02–1.85) after the campaigns.ConclusionOut-of-sequence vaccinations with DTP and MV are associated with higher mortality than MV as most recent vaccination; the effect is unlikely to be due to confounding. Hence, the reduction in out-of-sequence vaccinations may have lowered child mortality. It is recommended not to give DTP with MV or DTP after MV.     

Benefits of routine immunizations on childhood survival in Tari, Southern Highlands Province, Papua New Guinea

BACKGROUND: Non-specific beneficial as well as deleterious effects of childhood immunizations have been reported in areas of high mortality. This study aimed to determine the effects of diphtheria-tetanus-whole-cell-pertussis (DTP), BCG, hepatitis B, and measles vaccines on mortality in the highlands of Papua New Guinea (PNG). METHODS: Demographic events for children born in 1989-1994 who were under monthly demographic surveillance in Tari were recorded from birth until age 2 years, out-migration, death, or the end of the study period. Data on BCG, hepatitis B, DTP, measles and pneumococcal polysaccharide vaccination were collected monthly from clinic records. To allow for different characteristics of immunized and non-immunized children, analysis included conditioning on a propensity score for vaccination, adjusting for differences in children's background characteristics. RESULTS: In all, 101/3502 children (3%) who had at least one vaccine died between ages 29 days and 24 months were compared to 112/546 (21%) who had none. BCG was associated with lower mortality in the 1-5 month age group (hazard ratio [HR] = 0.17, 95% CI: 0.09, 0.34), measles vaccine with lower mortality at age 6-11 months (HR = 0.42, 95% CI: 0.17, 1.01), and pneumococcal polysaccharide vaccine with lower mortality at age 12-23 months (HR = 0.42, 95% CI: 0.19, 0.93). One or more doses of DTP was associated with lower overall mortality (HR = 0.27, 95% CI: 0.16, 0.44), particularly in the 1-5 month age group (HR = 0.19, 95% CI: 0.10, 0.34), and also in those who had had prior BCG (HR = 0.45, 95% CI: 0.22, 0.91). CONCLUSION: Routine immunizations are effective in reducing overall mortality in young children in an area of high mortality. In particular, DTP, whether considered separately or in addition to BCG, was associated with a lowering of overall mortality, in contrast to findings reported from Guinea-Bissau.     

Exploring the effects of BCG vaccination in patients diagnosed with tuberculosis: Observational study using the Enhanced Tuberculosis Surveillance system

BackgroundBacillus Calmette–Guérin (BCG) is one of the most widely-used vaccines worldwide. BCG primarily reduces the progression from infection to disease, however there is evidence that BCG may provide additional benefits. We aimed to investigate whether there is evidence in routinely-collected surveillance data that BCG vaccination impacts outcomes for tuberculosis (TB) cases in England.MethodsWe obtained all TB notifications for 2009–2015 in England from the Enhanced Tuberculosis surveillance system. We considered five outcomes: All-cause mortality, death due to TB (in those who died), recurrent TB, pulmonary disease, and sputum smear status. We used logistic regression, with complete case analysis, to investigate each outcome with BCG vaccination, years since vaccination and age at vaccination, adjusting for potential confounders. All analyses were repeated using multiply imputed data.ResultsWe found evidence of an association between BCG vaccination and reduced all-cause mortality (aOR:0.76 (95%CI 0.64–0.89), P:0.001) and weak evidence of an association with reduced recurrent TB (aOR:0.90 (95%CI 0.81–1.00), P:0.056). Analyses using multiple imputation suggested that the benefits of vaccination for all-cause mortality were reduced after 10 years.ConclusionsWe found that BCG vaccination was associated with reduced all-cause mortality in people with TB although this benefit was less pronounced more than 10 years after vaccination. There was weak evidence of an association with reduced recurrent TB.     

Predictors of pneumococcal vaccination among Australian adults at high risk of pneumococcal disease

BackgroundAlthough nearly all Australian children are vaccinated against pneumococcal disease, pneumococcal vaccine uptake is low among high-risk adults. This study aimed to identify perceived barriers to pneumococcal vaccination among high-risk adults.MethodsThis paper reports combined data on pneumococcal vaccination collected from three different online, cross-sectional surveys that were administered in Australia between August 2019 and September 2020. Using Poisson regression, we identified characteristics and beliefs associated with self-reported pneumococcal vaccination among adults aged 65 and over or with chronic health conditions.ResultsThe weighted estimate for pneumococcal vaccine coverage was 24% for high-risk adults under 65 and 53% for adults aged 65 and over. Nearly half of those under 65 reported they had never heard of the pneumococcal vaccine, while 26% of those aged 65 and over had never heard of the vaccine. Among those under 65, pneumococcal vaccination was associated with high perceived disease susceptibility (PR = 1.97, 95% CI: 1.23, 3.18), not having heard of the pneumococcal vaccine (PR = 0.44, 95% CI: 0.28–0.69), awareness that their chronic health condition puts them at increased risk of pneumonia (PR = 2.44, 95% CI: 1.51–3.98), and having a doctor recommend the vaccine (PR = 3.02, 95% CI: 2.05–4.44). Among adults aged 65 and over, self-reported pneumococcal vaccination was associated with influenza vaccination in the previous 12 months (PR = 4.28, 95% CI: 2.85–6.44) and awareness that they are eligible for free pneumococcal vaccination (PR = 5.02, 95% CI: 2.34–10.77).ConclusionAwareness of pneumococcal vaccines was low among adults at high risk of pneumococcal disease, which appears to be contributing to low vaccine uptake. A doctor’s recommendation was associated with increased uptake of pneumococcal vaccine, so interventions should be developed to promote pneumococcal vaccine uptake in GP practices.