Healthy Vaccinee Effect Research Articles

Biases in COVID-19 vaccine effectiveness studies using cohort design

Observational studies on COVID-19 vaccine effectiveness (VE) have provided critical real-world data, informing public health policy globally. These studies, primarily using pre-existing data sources, have been indispensable in assessing VE across diverse populations and developing sustainable vaccination strategies. Cohort design is frequently employed in VE research. The rapid implementation of vaccination campaigns during the COVID-19 pandemic introduced differential vaccination influenced by sociodemographic disparities, public policies, perceived risks, health-promoting behaviors, and health status, potentially resulting in biases such as healthy user bias, healthy vaccinee effect, frailty bias, differential depletion of susceptibility bias, and confounding by indication. The overwhelming burden on healthcare systems has escalated the risk of data inaccuracies, leading to outcome misclassifications. Additionally, the extensive array of diagnostic tests used during the pandemic has also contributed to misclassification biases. The urgency to publish quickly may have further influenced these biases or led to their oversight, affecting the validity of the findings. These biases in studies vary considerably depending on the setting, data sources, and analytical methods and are likely more pronounced in low- and middle-income country (LMIC) settings due to inadequate data infrastructure. Addressing and mitigating these biases is essential for accurate VE estimates, guiding public health strategies, and sustaining public trust in vaccination programs. Transparent communication about these biases and rigorous improvement in the design of future observational studies are essential.

Healthy vaccinee effect: a bias not to be forgotten in observational studies on COVID-19 vaccine effectiveness.

Healthy vaccinee effect: a bias not to be forgotten in observational studies on COVID-19 vaccine effectiveness.

Does the healthy vaccinee bias rule them all? Association of COVID-19 vaccination status and all-cause mortality from an analysis of data from 2.2 million individual health records

ObjectivesWe investigated the validity of claims of the healthy vaccinee effect (HVE) in COVID-vaccine studies by analyzing associations between all-cause mortality (ACM) and COVID-19 vaccination status. MethodsApproximately 2.2 million individual records from two Czech health insurance companies were retrospectively analyzed. Each age group was stratified according to the vaccination status (unvaccinated vs. individuals less than 4 weeks vs. more than 4 weeks from Doses 1, 2, 3, and 4 or more doses of vaccine). ACMs in these groups were computed and compared. ResultsConsistently over datasets and age categories, ACM was substantially lower in the vaccinated than unvaccinated groups regardless of the presence or absence of a wave of COVID-19 deaths. Moreover, the ACMs in groups more than 4 weeks from Doses 1, 2, or 3 were consistently several times higher than in those less than 4 weeks from the respective dose. HVE appears to be the only plausible explanation for this, which is further corroborated by a created mathematical model. ConclusionsIn view of the presence of HVE, the baseline difference in the frailty of vaccinated and unvaccinated populations in periods without COVID-19 must be taken into account when estimating COVID-19 vaccine effectiveness from observational data.

Effectiveness of COVID-19 Vaccination in Preventing All-Cause Mortality among Adults during the Third Wave of the Epidemic in Hungary: Nationwide Retrospective Cohort Study.

Our investigation aimed to describe the all-cause mortality rates by COVID-19 vaccination groups in Hungary for an epidemic period (1 April 2021–20 June 2021) and a nonepidemic period (21 June 2021–15 August 2021), and to determine the vaccines’ effectiveness in preventing all-cause mortality utilizing nonepidemic effectiveness measures to adjust for the healthy vaccinee effect (HVE). Sociodemographic status, comorbidity, primary care structural characteristics, and HVE-adjusted survival difference between fully vaccinated and unvaccinated cohorts in the epidemic period had been computed by Cox regression models, separately for each vaccine (six vaccines were available in Hungary). Hazard ratio (HR) reduction in epidemic period corrected with nonepidemic period’s HR with 95% confidence interval for each vaccine was used to describe the vaccine effectiveness (VE). The whole adult population (N = 6,404,702) of the country was followed in this study (4,026,849 fully vaccinated). Each vaccine could reduce the HVE-corrected all-cause mortality in the epidemic period (VEOxford/AstraZeneca = 0.592 [0.518–0.655], VEJanssen = 0.754 [0.628–0.838], VEModerna = 0.573 [0.526–0.615], VEPfizer-BioNTech = 0.487 [0.461–0.513], VESinopharm = 0.530 [0.496–0.561], and VESputnik V = 0.557 [0.493–0.614]). The HVE-corrected general mortality for COVID-19 vaccine cohorts demonstrated the real-life effectiveness of vaccines applied in Hungary, and the usefulness of this indicator to convince vaccine hesitants.

Risk of Immune Thrombocytopenia Induced By Influenza Vaccine. a Nationwide Population-Based Study in France

Introduction: Epidemiological studies suggest a risk of immune thrombocytopenia (ITP) following viral infections, particularly influenza. Conversely, an increased risk of ITP following vaccination has been proven for some vaccines like Measles-Mumps-Rubella vaccine. However, the risk of ITP induced by influenza vaccine is debated. Two case-controls studies has been conducted, with contradictory results: in the Berlin Case-Control Surveillance Study, an increased risk has been found (odds ratio - OR: 3.8 [95% confidence interval - CI: 1.5- 9.1]. Conversely, the French PGRx study suggested the absence of risk of ITP after influenza vaccination [OR: 0.9; 95% CI: 0.4-2.1]. These studies were limited by the number of ITP patients included (169 and 198, respectively) and other limitations. Therefore, we aimed to assess the risk of ITP induced by influenza vaccine in a nationwide cohort in France. Methods: We conducted a population-based study in France within the FAITH cohort (NCT03429660). This cohort is built within the National Health Database that links sociodemographic, hospital and out-hospital data. The FAITH cohort includes all adult patients with incident ITP in France since 2009. Patients are identified using a validated algorithm combining diagnosis codes and drug exposures (with very high positive predictive values). We included in the present study all patients with incident primary ITP aged ≥65 years at ITP diagnosis (indication of influenza vaccination in the general population in France) between July 2009 and June 2015. We assessed the link between influenza vaccine and ITP onset using two designs: a case-control and a self-controlled case series designs. In the case-control design, ITP cases were matched with four controls from the general population for age, sex and place of residency. Index dates for controls were similar to index dates of their matched cases. Cases and controls were compared for exposure to influenza vaccine in the 6 weeks before the index date using conditional logistic regression models adjusted for exposure to other drugs known as inducers of ITP. In the self-controlled case series study, only vaccinated ITP cases were included. The analysis compared the incidence of ITP within periods of risk (6 weeks following vaccination) to the incidence of ITP within other periods of time. We further excluded the 2 weeks prior to vaccine dispensing from the analysis to address selective survival bias (healthy vaccinee effect). Incidence rate ratios (IRRs) adjusted for seasonality were calculated. Results: We included 3,142 incident primary ITP patients aged ≥65 years matched with 12,528 controls in the case-control study. Overall, 147 cases (4.7%) and 579 controls (4.6%) were vaccinated with influenza vaccine during the 6 weeks prior to the index date (adjusted OR: 0.99; 95% CI: 0.80-1.23]). In the self-controlled case series study, 1,875 vaccinated ITP cases were included. Among them, 146 (7.8%) patients were diagnosed for ITP during one of the risk periods following vaccination. The adjusted IRR was 0.96 [95 CI%: 0.80-1.17]. Conclusion: This nationwide population-based study using two different designs showed no increased risk of ITP after influenza vaccination. Disclosures Moulis: Novartis pharma: Research Funding, Speakers Bureau; Amgen pharma: Research Funding, Speakers Bureau; CSL Behring: Research Funding.

The risk of non-specific hospitalised infections following MMR vaccination given with and without inactivated vaccines in the second year of life. Comparative self–controlled case-series study in England

Observational cohort studies in high-income settings have suggested that vaccination order may affect children’s subsequent risk of a heterologous infection, with live vaccines reducing and inactivated vaccines (given on their own or with a live vaccine), increasing the risk. We used the self-controlled case-series method, which automatically controls for the individual level confounding to which such cohort studies are prone, to test this hypothesis. We compared the relative incidence (RI) of infections post-vaccination in two calendar periods in England; in Period 1 (September 2002–August 2006) live measles, mumps, rubella (MMR) vaccine was given on its own and in Period 2 (September 2006–April 2010) inactivated vaccines (7-valent pneumococcal conjugate vaccine (PCV7) and sometimes the combined Haemophilus influenzae type b/meningococcal group C vaccine (Hib-MenC)) were given concomitantly with MMR. Admissions for an infection of the upper or lower respiratory tract, gastrointestinal system or other site in children aged 11–23 months were selected from the Hospital Episode Statistics database in England and linked to child health immunisation histories. The analysis included a total of 24,144 infections in 21,067 children in Period 1 and 36,880 in 31,616 children in Period 2. The RI of admission for any infection in Period 1 was 1.00 (95% confidence interval 0.95–1.06) compared with 0.95 (95% confidence interval 0.90–1.00) in Period 2. Comparing the two periods showed no evidence of a difference in the relative incidence estimates with a ratio of RI of 0.94 (95% confidence interval 0.87–1.02), RIs within 90 days of vaccination were 0.94 (0.91–0.97) in Period 1 and 0.94 (0.91–0.97) in Period 2, consistent with a temporary healthy vaccinee effect. In conclusion, we found no evidence to support the hypothesis that there is a reduction in heterologous infections after MMR on its own or an increase after MMR given concomitantly with an inactivated vaccine.

Risk of Vaccine-Induced Immune Thrombocytopenia in Children. Nationwide Case Cross-over and Self-Controlled Case Series Studies in France

Introduction: The association of measles, mumps and rubella (MMR) vaccination with immune thrombocytopenia (ITP) occurrence has been shown. The risk of ITP with other vaccines is still not known. This study was aimed at assessing the association of recommended vaccinations in children with ITP occurrence.Methods: We conducted a population-based study in France including all children newly diagnosed for primary ITP between July 2009 and June 2015. This cohort was built using a validated algorithm in the nationwide French health insurance database (SNDS). We assessed the risk of ITP with MMR vaccine, all combined vaccines containing diphtheria, tetanus and poliomyelitis (DTP) vaccines, pneumococcal and meningococcal C vaccines. We used two self-controlled designs: a case cross-over and a self-controlled case series. For the case cross-over, we compared the frequency of exposure to vaccines during a 6-week period immediately preceding the event (case period) with the frequency of exposure during a previous time period (control period, having the same duration as the case period). We performed sensitivity analyses using 8- and 12-week periods. Analyses were adjusted for exposure to other drugs known as inducers of ITP and seasonality. Odds ratios (OR) and their 95% confidence intervals (CI) were calculated. For the self-controlled case series, we compared the ITP incidence within periods of risk (following vaccination, named exposure period) with the incidence within the control period of non-exposure. The exposure period was defined by the 6 weeks after the vaccine dispensing in the principal analysis (8 and 12 weeks in sensitivity analyses). We further excluded the 2 weeks prior to vaccine dispensing from the non-exposure period to address selective survival bias (healthy vaccinee effect). The observation period was censored at ITP occurrence, due to variation of vaccination probability after ITP diagnosis and to the impossibility to distinguish ITP relapses from chronic ITP in the database. Analyses were adjusted for seasonality. Incidence rate ratios (IRRs) and their 95% CI were calculated. We assessed the exposure to each vaccine, and conducted subgroup analyses in patients without any concurrent vaccination during case and control periods for the case cross-over study and exposure periods for the self-controlled case series study. We also calculated the number of ITP cases occurring during the 6 weeks after vaccination divided by the number of vaccine doses dispensed in the French children population during the study period.Results: We included 2,549 newly diagnosed primary ITP children. Among them, median age was 5.1 years and 46.5 % were females; 41.4% had been exposed to at least one studied vaccine before ITP onset. The results of the principal analysis are detailed in the Table. There was an increased occurrence of ITP following MMR vaccination (OR: 1.60, 95% CI: 1.09-2.34; IRR: 1.30, 95% CI: 0.95-1.80). Analyses excluding the patients with concurrent vaccination, notably meningococcal vaccination, led to similar results (OR: 1.66, 95% CI: 1.02-2.71; IRR: 1.39, 95% CI: 0.80-2.42). There was also an increased occurrence of ITP with the meningococcal C vaccine (OR: 1.92, 95% CI: 0.95-3.86; IRR: 1.40, 95% CI: 0.86-2.29). Analyses conducted in patients without any concurrent vaccination, notably MMR vaccination, confirmed these results with wide 95% CI because of fewer patients included (OR: 1.64, 95% CI: 0.57-4.71; IRR: 1.64, 95% CI: 0.69-3.86). No association was observed between other vaccines and ITP occurrence. The numbers of ITP cases occurring in the 6 weeks following vaccination per million doses dispensed were 8.2 for pneumococcal, 9.2 for DTP, 9.6 for meningococcal and 11.5 for MMR vaccines. Of note, these numbers overestimate the probability of vaccine-induced ITP. Indeed, they are ITP cases chronologically compatible with vaccine adverse reaction without any individual causality assessment (a worst-case scenario considering that all cases were triggered by vaccines).Conclusion: This study showed an increased occurrence of ITP after MMR and meningococcal C vaccines. It is reassuring for other vaccines. We cannot exclude temporal association with MMR and meningococcal C vaccines due to the peak of ITP incidence at 12 months of age in the general population. However, vaccine-induced ITP is a very rare event, which does not cast doubt on the interest of vaccination. DisclosuresNo relevant conflicts of interest to declare.

The use of relative incidence ratios in self-controlled case series studies: an overview.

BackgroundThe self-controlled case series (SCCS) is a useful design for investigating associations between outcomes and transient exposures. The SCCS design controls for all fixed covariates, but effect modification can still occur. This can be evaluated by including interaction terms in the model which, when exponentiated, can be interpreted as a relative incidence ratio (RIR): the change in relative incidence (RI) for a unit change in an effect modifier.MethodsWe conducted a scoping review to investigate the use of RIRs in published primary SCCS studies, and conducted a case-study in one of our own primary SCCS studies to illustrate the use of RIRs within an SCCS analysis to investigate subgroup effects in the context of comparing whole cell (wcp) and acellular (acp) pertussis vaccines. Using this case study, we also illustrated the potential utility of RIRs in addressing the healthy vaccinee effect (HVE) in vaccine safety surveillance studies.ResultsOur scoping review identified 122 primary studies reporting an SCCS analysis. Of these, 24 described the use of interaction terms to test for effect modification. 21 of 24 studies reported stratum specific RIs, 22 of 24 reported the p-value for interaction, and less than half (10 of 24) reported the estimate of the interaction term/RIR, the stratum specific RIs and interaction p-values. Our case-study demonstrated that there was a nearly two-fold greater RI of ER visits and admissions following wcp vaccination relative to acp vaccination (RIR = 1.82, 95 % CI 1.64–2.01), where RI estimates in each subgroup were clearly impacted by a strong healthy vaccinee effect.ConclusionsWe demonstrated in our scoping review that calculating RIRs is not a widely utilized strategy. We showed that calculating RIRs across time periods is useful for the detection of relative changes in adverse event rates that might otherwise be missed due to the HVE. Many published studies of vaccine-associated adverse events could have missed/underestimated important safety signals masked by the HVE. With further development, our application of RIRs could be an important tool to address the HVE, particularly in the context of self-controlled study designs.

Mortality Rates and Cause-of-Death Patterns in a Vaccinated Population

Determining the baseline mortality rate in a vaccinated population is necessary to be able to identify any unusual increases in deaths following vaccine administration. Background rates are particularly useful during mass immunization campaigns and in the evaluation of new vaccines. Provide background mortality rates and describe causes of death following vaccination in the Vaccine Safety Datalink (VSD). Analyses were conducted in 2012. Mortality rates were calculated at 0-1 day, 0-7 days, 0-30 days, and 0-60 days following vaccination for deaths occurring between January 1, 2005, and December 31, 2008. Analyses were stratified by age and gender. Causes of death were examined, and findings were compared to National Center for Health Statistics (NCHS) data. Among 13,033,274 vaccinated people, 15,455 deaths occurred between 0 and 60 days following vaccination. The mortality rate within 60 days of a vaccination visit was 442.5 deaths per 100,000 person-years. Rates were highest in the group aged ≥85 years, and increased from the 0-1-day to the 0-60-day interval following vaccination. Eleven of the 15 leading causes of death in the VSD and NCHS overlap in both systems, and the top four causes of death were the same in both systems. VSD mortality rates demonstrate a healthy vaccinee effect, with rates lowest in the days immediately following vaccination, most apparent in the older age groups. The VSD mortality rate is lower than that in the general U.S. population, and the causes of death are similar.

Patterns of emergency room visits, admissions and death following recommended pediatric vaccinations—A population based study of 969,519 vaccination events

Background The risk of immediate adverse events due to the inflammation created by a vaccine is a potential concern for pediatric vaccine programs. Methods We analyzed data on children born between March 2006 and March 2009 in the province of Ontario. Using the self-controlled case series design, we examined the risk of the combined endpoint of emergency room visit and hospital admission in the immediate 3 days post vaccination to a control period 9–18 days after vaccination. We examined the end points of emergency room visits, hospital admissions and death separately as secondary outcomes. Results We examined 969,519 separate vaccination events. The relative incidence of our combined end point was 0.85 (0.80–0.90) for vaccination at age 2 months, 0.74 (0.69–0.79) at age 4 months and 0.68 (0.63–0.72) at age 6 months. The relative incidence was reduced for the individual endpoints of emergency room visits, admissions and death. There were 5 or fewer deaths in the risk interval of all 969,519 vaccination events. In a post hoc analysis we observed a large reduction in events in the immediate 3 days prior to vaccination suggesting a large healthy vaccinee effect. Conclusion There was no increased incidence of the combined end point of emergency room visits and hospitalizations in the 3-day period immediately following vaccination, nor for individual endpoints or death. The health vaccinee effect could create the perception of worsening health following vaccines in the absence of any vaccine adverse effect and could also mask an effect in the immediate post-vaccination period.

Do immunisations reduce the risk for SIDS? A meta-analysis

There are claims that immunisations cause sudden infant death syndrome (SIDS), but some studies have found either no association or that they are associated with a reduced risk of SIDS. To conduct a meta-analysis examining the relationship between immunisation and SIDS. Nine case-controls studies were identified examining this association, of which four adjusted for potential confounders. The summary odds ratio (OR) in the univariate analysis suggested that immunisations were protective, but the presence of heterogeneity makes it difficult to combine these studies. The summary OR for the studies reporting multivariate ORs was 0.54 (95% CI=0.39-0.76) with no evidence of heterogeneity. Immunisations are associated with a halving of the risk of SIDS. There are biological reasons why this association may be causal, but other factors, such as the healthy vaccinee effect, may be important. Immunisations should be part of the SIDS prevention campaigns.