Vaccinology: time to change the paradigm? Benn, Christine Stabell; Fisker, Ane B; Rieckmann, Andreas ...
The Lancet infectious diseases,
October 2020, 2020-10-00, 20201001, Letnik:
20, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The existing vaccine paradigm assumes that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of total ...mortality, and that the effects of vaccines are similar for males and females. However, epidemiological vaccine research has generated observations that contradict these assumptions and suggest that vaccines have important non-specific effects on overall health in populations. These include the observations that several live vaccines reduce the incidence of all-cause mortality in vaccinated compared with unvaccinated populations far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased all-cause mortality in females. In this Personal View we describe current observations and contradictions and define six emerging principles that might explain them. First, that live vaccines enhance resistance towards unrelated infections. Second, non-live vaccines enhance the susceptibility of girls to unrelated infections. Third, the most recently administered vaccination has the strongest non-specific effects. Fourth, combinations of live and non-live vaccines given together have variable non-specific health effects. Fifth, vaccinating children with live vaccines in the presence of maternal immunity enhances beneficial non-specific effects and reduces mortality. Finally, vaccines might interact with other co-administered health interventions, for example vitamin A supplementation. The potential implications for child health are substantial. For example, if BCG vaccination was given to children at birth, if higher measles vaccination coverage could be obtained, if diphtheria, tetanus, and pertussis-containing vaccines were not given with or after measles vaccine, or if the BCG strain with the best non-specific effects could be used consistently, then child mortality could be considerably lower. Pursuing these emerging principles could improve our understanding and use of vaccines globally.
Ten years ago, we formulated two hypotheses about whole-cell diphtheria-tetanus-pertussis (DTP) vaccination: first, when given after BCG, DTP increases mortality in girls and, second, following DTP ...there is an increase in the female/male mortality rate ratio (MRR). A recent review by WHO found no convincing evidence that DTP increases mortality in females.
We used previous DTP reviews as well as the recent WHO review for assessing the hypotheses. As pre-specified we excluded studies with survival or frailty bias; if children had received BCG and DTP simultaneously; and if the children had received neonatal vitamin A.
In seven studies of BCG-vaccinated children, DTP vaccination was associated with a 2.54 (95% CI 1.68-3.86) increase in mortality in girls (with no increase in boys ratio 0.96, 0.55-1.68). In 10 studies of BCG-vaccinated children, the female-to-male mortality ratio was 2.45 (1.48-4.06) times higher after DTP than before DTP. In 15 studies of children who had received DTP after previous BCG vaccination, mortality was 1.53 (1.21-1.93) times higher in girls than boys. The findings were similar in studies conducted before and after formulation of the hypotheses.
The two hypotheses were confirmed in the studies that fulfilled pre-specified criteria.
By contrast, DTP is associated with increased female mortality. 5 Both the "yes" and "no" side state that the time for randomised trials has passed, as it is not ethical to deprive children of a ...vaccine that is part of the recommended schedule. 6 The Strategic Advisory Group of Experts on Immunization (SAGE) recently reviewed the evidence for the non-specific effects of BCG, DTP, and MV on all cause child mortality and recommended further research and where possible randomised trials. 7 With the limited evidence behind the current timing, and an increasing amount of evidence documenting that changes to the current schedule may improve child health, there should be equipoise for studies evaluating alternative schedules.
Objective
Improving civil registration and vital statistics (CRVS) systems is essential to monitoring health objectives locally and globally. The barriers to birth and particularly death registration ...in low‐ and middle‐income countries are however poorly understood.
Methods
We conducted a survey among women of reproductive age in Bissau, the capital of Guinea‐Bissau. We asked women with a birth in the past two years whether their child had been registered and had obtained a birth certificate. We elicited the sources of information about birth registration and asked respondents to list their reasons for (not) registering a birth. If their child had died, we asked similar questions about death registration.
Results
Most women (86%) had received messages about birth registration, but few women whose child had died had heard about the need to register deaths (22%). The primary sources of information about birth registration were messages broadcast on the radio or displayed at health facilities. Information about death registration was primarily obtained through informal social networks. Only 16% of births, and 2% of deaths, had been registered. The main barriers to birth registration were administrative pre‐requisites and paternal absence. The main reasons for not registering a death were lack of knowledge about death registration and lack of perceived benefits.
Conclusion
Strengthening CRVS systems requires addressing the specific barriers preventing birth and death registration. In Bissau, interventions to improve knowledge about death registration are needed. Simplifying registration procedures, as well as providing additional incentives, might help improve the coverage of birth registration.
Objectif
L'amélioration des systèmes d’état civil et des statistiques de l’état civil (CRVS) est essentielle pour le suivi des objectifs de santé aux niveaux local et mondial. Les obstacles à l'enregistrement des naissances et en particulier à celui des décès dans les pays à revenu faible et intermédiaire sont cependant mal compris.
Méthodes
Nous avons mené une enquête auprès des femmes en âge de procréer à Bissau, capitale de la Guinée‐Bissau. Nous avons demandé aux femmes ayant eu une naissance au cours des deux dernières années si leur enfant avait été enregistré et avait obtenu un acte de naissance. Nous avons recherché les sources d'information sur l'enregistrement des naissances et avons demandé aux personnes interrogées d'indiquer les raisons pour ne pas enregistrer une naissance. Si leur enfant était décédé, nous avons posé des questions similaires sur l'enregistrement des décès.
Résultats
La plupart des femmes (86%) avaient reçu des messages sur l'enregistrement des naissances, mais peu de femmes dont l'enfant était décédé avaient entendu parler de la nécessité d'enregistrer les décès (22%). Les principales sources d'information sur l'enregistrement des naissances étaient des messages diffusés à la radio ou dans des établissements de santé. Les informations sur l'enregistrement des décès ont été principalement obtenues via des réseaux sociaux informels. Seules 16% des naissances et 2% des décès ont été enregistrés. Les principaux obstacles à l'enregistrement des naissances étaient les prérequis administratifs et l'absence paternelle. Les principales raisons pour ne pas enregistrer un décès étaient le manque de connaissances sur l'enregistrement des décès et le manque des avantages perçus.
Conclusion
Renforcer les systèmes CRVS nécessite de s'attaquer aux obstacles spécifiques empêchant l'enregistrement des naissances et des décès. A Bissau, des interventions visant à améliorer les connaissances sur l'enregistrement des décès sont nécessaires. La simplification des procédures d'enregistrement, ainsi que la mise en place d'incitations supplémentaires, pourraient contribuer à améliorer la couverture de l'enregistrement des naissances.
•Measles vaccine (MV) may reduce mortality and admissions beyond measles prevention.•For decades, MV has been distributed in campaigns to eliminate measles worldwide.•We assessed an MV campaign's ...effect in a cluster-randomized trial in Guinea-Bissau.•Mortality was lower than anticipated and MV did not reduce mortality or admissions.•MV's effects may differ by underlying disease patterns and other vaccine campaigns.
Campaigns with measles vaccine (C-MV) are conducted to eradicate measles, but prior studies indicate that MV reduces non-measles mortality and hospital admissions too. We hypothesized that C-MV reduces death/hospital admission by 30%.
Between 2016-2019, we conducted a non-blinded cluster-randomized trial randomizing village clusters in rural Guinea-Bissau to a C-MV targeting children aged 9-59 months. In Cox proportional hazards models, we assessed the effect of C-MV, obtaining hazard ratios (HR) for the composite outcome (death/hospital admission). We also examined potential effect modifiers.
Among 18,411 children (9636 in 111 intervention clusters/8775 in 110 control clusters), 379 events occurred (208 intervention/171 control) during a median follow-up period of 22 months. C-MV did not reduce the composite outcome (HR 1.12, 95% confidence interval 0.88-1.41). Mortality among enrolled children (5.3 intervention and 4.6 control, per 1000 person-years) was approximately half the pre-trial mortality rate (11.1 intervention and 8.9 control, per 1000 person-years). Neither planned nor explorative analyses of potential effect modifiers explained the contrasting results to prior studies.
C-MV did not reduce overall mortality or hospital admission. This might be explained by changes in disease patterns, baseline differences in health status, and/or modifying effects of other campaigns during follow-up.
Though still high, the infant mortality rate in Guinea-Bissau has declined. We aimed to identify risk factors including vaccination coverage, for infant mortality in the rural population of ...Guinea-Bissau and assess whether these risk factors changed from 1992-3 to 2002-3.
The Bandim Health Project (BHP) continuously surveys children in rural Guinea-Bissau. We investigated the association between maternal and infant factors (especially DTP and measles coverage) and infant mortality. Hazard ratios (HR) were calculated using Cox regression. We tested for interactions with sex, age groups (defined by current vaccination schedule) and cohort to assess whether the risk factors were the same for boys and girls, in different age groups in 1992-3 and in 2002-3.
The infant mortality rate declined from 148/1000 person years (PYRS) in 1992-3 to 124/1000 PYRS in 2002-3 (HR = 0.88;95%CI:0.77-0.99); this decline was significant for girls (0.77;0.64-0.94) but not for boys (0.97;0.82-1.15) (p = 0.10 for interaction). Risk factors did not differ significantly by cohort in either distribution or effect. Mortality decline was most marked among girls aged 9-11 months (0.56;0.37-0.83). There was no significant mortality decline for girls 1.5-8 months of age (0.93;0.68-1.28) (p = 0.05 for interaction). DTP and measles coverage increased from 1992-3 to 2002-3.
Risk factors did not change with the decline in mortality. Due to beneficial non-specific effects for girls, the increased coverage of measles vaccination may have contributed to the disproportional decline in mortality by sex and age group.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Live vaccines against measles (MV), tuberculosis (BCG), polio (OPV) and smallpox reduce mortality more than explained by target-disease prevention. The beneficial nonspecific effects (NSEs) of MV are ...strongest when MV is given in presence of maternal antibodies. We therefore hypothesised that revaccination in presence of prior immunity enhances beneficial NSEs.
Literature search for studies of revaccination and mortality.
In two randomised trials (RCTs), two doses versus one dose of MV reduced all-cause mortality by 63% (95% CI: 23–83%) from 9 to 18months of age. In a quasi-experimental study two doses before and after 9months compared with one dose of MV after 9months of age reduced mortality by 59% (25–81%). BCG-revaccination significantly enhanced BCG's effect against overall child mortality in two RCTs. In a natural experiment study of OPV campaigns over a 13-year-period in Guinea-Bissau, each additional dose of OPV was associated with a 13% (4–21%) reduction in mortality rate. The beneficial NSEs of smallpox vaccination for survival increased significantly with the number of smallpox vaccination scars.
Revaccination with live vaccines led to substantial reductions in overall mortality. These findings challenge current understanding of vaccines and may explain the beneficial effects of campaigns with live vaccines.
•Live vaccines may have beneficial nonspecific effect protecting against more than the target disease.•Revaccination with vaccines against measles, tuberculosis, polio and smallpox should have limited effect on survival.•Nonetheless, revaccination with these vaccines indicate major reductions in all-cause mortality.
Live vaccines against measles, tuberculosis, polio, and smallpox reduce mortality more than explained by prevention of the target-disease. Hence, these vaccines train the immune system to protection against unrelated infections. The beneficial nonspecific effect is enhanced when vaccination takes place in presence of maternal immunity. We therefore examined whether revaccination with the live vaccines against measles, tuberculosis, polio and smallpox boosted their beneficial nonspecific effects. Though limited, existing scientific literature supports that revaccination enhances the beneficial nonspecific effects of these four vaccines. The implications are potentially major; overall mortality could be reduced significantly with increasing use of revaccination with live vaccines.
Risks of neonatal death, stillbirth and miscarriage are highest in low- and middle-income countries (LMICs), where data has most gaps and estimates rely on household surveys, dependent on women ...reporting these events. Underreporting of pregnancy and adverse pregnancy outcomes (APOs) is common, but few studies have investigated barriers to reporting these in LMICs. The EN-INDEPTH multi-country study applied qualitative approaches to explore barriers and enablers to reporting pregnancy and APOs in surveys, including individual, community, cultural and interview level factors.
The study was conducted in five Health and Demographic Surveillance System sites in Guinea-Bissau, Ethiopia, Uganda, Bangladesh and Ghana. Using an interpretative paradigm and phenomenology methodology, 28 focus group discussions were conducted with 82 EN-INDEPTH survey interviewers and supervisors and 172 women between February and August 2018. Thematic analysis was guided by an a priori codebook.
Survey interview processes influenced reporting of pregnancy and APOs. Women found questions about APOs intrusive and of unclear relevance. Across all sites, sociocultural and spiritual beliefs were major barriers to women reporting pregnancy, due to fear that harm would come to their baby. We identified several factors affecting reporting of APOs including reluctance to speak about sad memories and variation in recognition of the baby's value, especially for APOs at earlier gestation. Overlaps in local understanding and terminology for APOs may also contribute to misreporting, for example between miscarriages and stillbirths. Interviewers' skills and training were the keys to enabling respondents to open up, as was privacy during interviews.
Sociocultural beliefs and psycho-social impacts of APOs play a large part in underreporting these events. Interviewers' skills, careful tool development and translation are the keys to obtaining accurate information. Reporting could be improved with clearer explanations of survey purpose and benefits to respondents and enhanced interviewer training on probing, building rapport and empathy.
Measles vaccination coverage in Guinea-Bissau is low; fewer than 80% of children are currently measles vaccinated before 12 months of age. The low coverage hampers control of measles. Furthermore, ...accumulating evidence indicates that measles vaccine has beneficial non-specific effects, strengthening the resistance towards other infections. Thus, even if children are not exposed to measles virus, measles-unvaccinated children may be worse off. To increase vaccination coverage, WHO recommends that contacts with the health system for mild illness are utilised to vaccinate. Currently, in Guinea-Bissau, curative health system contacts are not utilised.
Bandim Health Project registers out-patient consultations and admissions at the paediatric ward of the National Hospital in Guinea-Bissau. Measles-unvaccinated children aged 9-59 months consulting for milder illness or being discharged from the paediatric ward will be invited to participate in a randomised trial. Among 5400 children, randomised 1:1 to receive standard measles vaccine or a saline placebo, we will test the hypothesis that providing a measles vaccine at discharge lowers the risk of admission/mortality (composite outcome) during the subsequent 6 months by 25%. All enrolled children are followed through the Bandim Health Project registration system and through telephone follow-up. The first 1000 enrolled children are furthermore followed through interviews on days 2, 4, 7 and 14 after enrolment.
Utilising missed vaccination opportunities can increase vaccination coverage and may improve child health. However, without further evidence for the safety and potential benefits of measles vaccination, these curative contacts are unlikely to be used for vaccination in Guinea-Bissau.
www.
gov NCT04220671 . Registered on 5 January 2020.
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