Mirjam J. Knol’s research while affiliated with National Institute for Public Health and the Environment and other places

Background - Diagnostic (self-)testing for SARS-CoV-2 may lead to selection bias in test-negative case-control designs (TND) for COVID-19 vaccine effectiveness (CVE) at primary care level. We investigated whether after the acute phase of the pandemic, (self-)testing among those with an acute respiratory infection (ARI) was associated with healthcare seeking behaviour at primary care level in the general Dutch population. Methods - We pooled questionnaire data from three study rounds (June 2022, November 2022 & April 2023) of the nationwide PIENTER Corona cohort study. Among participants aged 18-91 years, we selected the first self-reported ARI episode, defined as cough, sore throat, dyspnoea and/or coryza, since March 2022. We performed log-binomial regression analyses adjusted for age, sex, educational level and comorbidities to assess associations between COVID-19 vaccination, SARS-CoV-2 (self-)testing and general practitioner (GP) consultation, and between GP consultation and prior (self-)test result. Results - Among 3152 participants with an ARI episode, vaccinated (vs unvaccinated) participants more often (self-)tested (adjusted RR [95% CI]: 1.07 [1.04-1.11]) or consulted a GP (1.57 [1.21-2.09]). (Self-)test result overall was not associated with GP consultation (0.86 [0.69-1.08]). Vaccination-stratified analyses showed vaccinated individuals were less likely to consult the GP after a positive (self-) test (0.62 [0.49-0.79]), while unvaccinated were more likely to (2.00 [1.08-3.51]). Conclusions - In this Dutch population-based cohort, GP consultation between May 2022 and March 2023 was differential by (self-)test result and vaccination status, indicating potential selection bias in TND CVE estimates from testing before GP consultation. More research to quantify this bias in various settings is needed.

In 2022, an increase in invasive group A streptococcal (iGAS) infections was observed in the Netherlands. A particular increase was seen among children; therefore, we aimed to assess risk factors for iGAS infection in children aged 6 months to 5 years. A prospective case–control study was conducted between February and May 2023. We approached parents of notified iGAS cases to complete a questionnaire on exposures during 4 weeks prior to disease onset. Controls were recruited via social media and matched to cases on sex and birthyear. Conditional logistic regression was performed to estimate odds ratios (OR) of exposures. For the analysis, we included 18 cases and 103 controls. Varicella prior to onset of iGAS disease was reported in two (11%) cases and one (1%) control (OR: 12.0, 95% CI: 1.1–139.0). Exposure to group A streptococcal (GAS)-like illnesses such as impetigo, pharyngitis, and scarlet fever was reported in 8 (44%) cases and 15 (15%) controls (OR: 7.1, 95% CI: 1.8–29.0). Our findings are in line with previous studies by identifying varicella as a risk factor for iGAS among young children and highlight the association with non-invasive GAS infections in the community as a possible source of transmission.

Fatigue is one of the most common persistent symptoms of SARS-CoV-2 infection. We aimed to assess fatigue during and after a SARS-CoV-2 infection by age, sex, presence of a medical risk condition, SARS-CoV-2 variant and vaccination status, accounting for pre-infection fatigue and compared with uninfected individuals. We used data from an ongoing prospective cohort study in the Netherlands (VASCO). We included 22,705 first infections reported between 12 July 2021 and 9 March 2024. Mean fatigue scores increased during infection, declined rapidly in the first 90 days post-infection, but remained elevated until at least 270 days for Delta and 120 days for Omicron infections. Prevalence of severe fatigue was 18.5% before first infection. It increased to 24.4% and 22.5% during acute infection and decreased to 21.2% and 18.9% at 90 days after Delta and Omicron infection, respectively. The prevalence among uninfected participants was lower than among matched Delta-infected participants during the acute phase of the infection and 90 days post-infection. For matched Omicron-infected individuals this was only observed during the acute phase. We observed no differences in mean post- vs pre-infection fatigue scores at 90-270 days post-infection by vaccination status. The impact of SARS-CoV-2 infection on the prevalence of severe fatigue was modest at population level, especially for Omicron.

Background The impact of human papillomavirus (HPV) vaccination programs depends on the degree of indirect protection against new infections achieved among unvaccinated women. We estimated the indirect effect of bivalent HPV vaccination by comparing the HPV-type incidence in unvaccinated female participants between a cohort offered vaccination in 2009/10 and a cohort of similar aged women offered vaccination in 2014. Methods We compared the incidence rates of HPV types in the HAVANA cohort (follow-up from 2010/11 until 2015/16) with those from the HAVANA-2 cohort (2017-2022) using two regression approaches to estimate the indirect effect of HPV vaccination. First, we calculated the incidence ratio (IRR) for a vaccine or cross-protective type in HAVANA-2 versus HAVANA by Poisson regression and compared it to the IRR for a non-cross-protective type. The indirect vaccine effect is defined as 1-ratio of the IRRs. Second, we performed Cox regression with infection by vaccine or cross-protective type as the endpoint and calculated the hazard ratio (HR) for HAVANA-2 versus HAVANA after adjusting for time-varying sociodemographic variables. The indirect effect is defined as 1-HR. Results We included 661 unvaccinated participants in HAVANA and 927 in HAVANA-2. We observed a significant reduction in incident HPV16 infections of 70.9% (95% CI 48.3-83.7%) with Poisson regression and of 73.1% (95% CI 53.3-84.5%) with Cox regression. For HPV45, significant decreases of 67.3% (95% CI 8.8-88.3%) and 69.8% (95% CI 15.2-89.3%) were observed. For HPV18, HPV31, and HPV33, the indirect effect was not statistically significant. Conclusions Large indirect effects of the bivalent HPV vaccination program were observed for HPV16 and HPV45 infections.

Background The protective effect of HPV vaccination against cervical cancer has been demonstrated in registry linkage studies. The start age of screening in those studies was lower than 25 years. We estimated the vaccine effectiveness of bivalent HPV16/18 vaccination against invasive cervical cancer and cervical intraepithelial neoplasia grade 3 (CIN3+) in the Netherlands where routine screening starts at age 30 years. Methods We linked the vaccination status of women born in year 1993 who were eligible for HPV vaccination at age 16 years with histopathological results recorded in the nationwide pathology databank (Palga). Cumulative risks of invasive cervical cancer and CIN3+ were estimated for fully vaccinated (3 doses or 2 doses ≥ 150 days apart), partially vaccinated, and unvaccinated women. Vaccine effectiveness estimates were adjusted for differences in screening participation between the vaccine groups. Findings A total of 103,059 women were included, of whom 47,130 were fully vaccinated, 5,098 were partially vaccinated, and 50,831 were unvaccinated. Five (0.011%) cancers were observed in fully vaccinated, two (0.039%) in partially vaccinated, and 42 (0.083%) in unvaccinated women. The vaccine effectiveness in fully vaccinated women was 91.5% (95% CI 78.9, 96.6) against cancer and 81.2% (95% CI 78.4, 83.7) against CIN3+. The vaccine effectiveness in partially vaccinated women was 48.1% (95% CI -56.8, 82.8) against cancer and 58.4% (95% CI 45.3, 68.3) against CIN3+. Interpretation The high effectiveness of bivalent HPV vaccination against cervical cancer and CIN3+ and the low cancer incidence supports a screening start age of 30 years in vaccinated women.

We assessed the validity of serum total anti-nucleoprotein Immunoglobulin (N-antibodies) to identify SARS-CoV-2 (re)infections by estimating the persistence of N-antibody seropositivity and boosting following infection. From a prospective Dutch cohort study (VASCO), we included adult participants with ≥2 consecutive self-collected serum samples, 4–8 months apart, between May 2021–May 2023. Sample pairs were stratified by N-seropositivity of the first sample and by self-reported infection within the sampling interval. We calculated the proportions of participants with N-seroconversion and fold-increase (1.5, 2, 3, 4) of N-antibody concentration over time since infection and explored determinants. We included 67,632 sample pairs. Pairs with a seronegative first sample (70%) showed 89% N-seroconversion after reported infection and 11% when no infection was reported. In pairs with a seropositive first sample (30%), 82%–65% showed a 1.5- to 4-fold increase with a reported reinfection, and 19%–10% without a reported reinfection, respectively. After one year, 83% remained N-seropositive post-first infection and 93%–61% showed a 1.5-fold to 4-fold increase post-reinfection. Odds for seroconversion/fold increase were higher for symptomatic infections and Omicron infections. In the current era with limited antigen or PCR testing, N-serology can be validly used to detect SARS-CoV-2 (re)infections at least up to a year after infection, supporting the monitoring of COVID-19 burden and vaccine effectiveness.

Introduction Most studies on risk factors for a SARS-CoV-2 infection were conducted in the pre-vaccination era with many non-pharmaceutical prevention measures in place. We investigated risk factors for symptomatic SARS-CoV-2 infections in vaccinated persons in a period with a varying degree of prevention measures. Methods In a test-negative case control study among vaccinated adults attending community COVID-19 testing locations between June 1st 2021 till February 28th 2022, we compared symptomatic cases with symptomatic controls (to study risk factors specific for SARS-CoV-2) and with asymptomatic controls (to study risk factors that could apply to respiratory infections in general). We examined potential risk factors including household composition and mitigation behaviour by logistic regression, adjusting for age, sex, and week of testing. Results Risk factors for a positive SARS-CoV-2 test when symptomatic cases were compared to symptomatic controls were: having a household size of more than 4 (adjusted odds ratio: 1.47; 95% CI 1.14–1.92), being a healthcare worker (1.27;1.18–1.47), and visiting busy locations outside (1.49;1.19–1.87). When symptomatic cases were compared to asymptomatic controls, a household size of more than 4 members (1.71;1.25–2.33), living with children aged 0–12 (1.59;1.12–2.26), visiting busy locations outside (1.64;1.24–2.17) were independent risk factors for a positive SARS-CoV-2 test. Risk factors for separate periods and waves differed from the study period as a whole. Conclusion This study was conducted in a period with a varying degree of prevention measures. Among vaccinated individuals, we identified several SARS-CoV-2 specific risk factors and SARS-CoV-2 risk factors that could be more general for respiratory infections. For SARS-CoV-2 transmission more attention could be given to visiting busy outdoor locations, having a household size that consists of more than 4 persons, being a healthcare worker, and living with children aged 0–12. Risk factors varied with different phases in the pandemic, emphasizing the importance of repeated assessment of risk factors.

This study explored the effect of SARS-CoV-2 infection and COVID-19 vaccination during pregnancy on neonatal outcomes among women from the general Dutch population. VASCO is an ongoing prospective cohort study aimed at assessing vaccine effectiveness of COVID-19 vaccination. Pregnancy status was reported at baseline and through regular follow-up questionnaires. As an extension to the main study, all female participants who reported to have been pregnant between enrolment (May–December 2021) and January 2023 were requested to complete an additional questionnaire on neonatal outcomes. Multivariable linear and logistic regression analyses were used to determine the associations between self-reported SARS-CoV-2 infection or COVID-19 vaccination during pregnancy and neonatal outcomes, adjusted for age, educational level, and presence of a medical risk condition. Infection analyses were additionally adjusted for COVID-19 vaccination before and during pregnancy, and vaccination analyses for SARS-CoV-2 infection before and during pregnancy. Of 312 eligible participants, 232 (74%) completed the questionnaire. In total, 196 COVID-19 vaccinations and 115 SARS-CoV-2 infections during pregnancy were reported. Infections were mostly first infections (86; 75%), caused by the Omicron variant (95; 83%), in women who had received ≥1 vaccination prior to infection (101; 88%). SARS-CoV-2 infection during pregnancy was not significantly associated with gestational age (β = 1.7; 95%CI: −1.6–5.0), birth weight (β = 82; −59 to 223), Apgar score <9 (odds ratio (OR): 1.3; 0.6–2.9), postpartum hospital stay (OR: 1.0; 0.6–1.8), or neonatal intensive care unit admission (OR: 0.8; 0.2–3.2). COVID-19 vaccination during pregnancy was not significantly associated with gestational age (β = −0.4; −4.0 to 3.2), birth weight (β = 88; −64 to 240), Apgar score <9 (OR: 0.9; 0.4–2.3), postpartum hospital stay (OR: 0.9; 0.5–1.7), or neonatal intensive care unit admission (OR: 1.6; 0.4–8.6). In conclusion, this study did not find an effect of SARS-CoV-2 infection or COVID-19 vaccination during pregnancy on any of the studied neonatal outcomes among a general Dutch, largely vaccinated, population. Together with data from other studies, this supports the safety of COVID-19 vaccination during pregnancy.

Background The innate immune response is important for the development of the specific adaptive immunity, however it may also be associated with reactogenicity after vaccination. We explore the association between innate responsiveness, reactogenicity, and antibody response after first COVID-19 vaccination. Methods We included 146 healthy Dutch individuals aged 12–59 who received their first BNT162b2 (Comirnaty, Pfizer) COVID-19 vaccination. Data on reactogenicity were collected for each individual through daily questionnaires from day 0–5 after vaccination. From 60 participants, serum (adults) and plasma (adolescents) samples were collected before and/or 2 ± 1 days after vaccination to measure cytokines/chemokines as markers for innate responsiveness. Each individual was categorised into innate low, intermediate and high responder based on above or below the median value for each analyte detected after vaccination. For 137 participants, serum was collected at day 28 after vaccination for Spike S1- and RBD-antibody concentration. The associations between reactogenicity and/or innate responsiveness and/or log-transformed antibody concentration were explored using logistic and linear regressions. Results Most participants (85 %) reported both local and systemic symptoms after vaccination. Two participants reported no symptoms. More than half (54 %) reported one or more moderate symptoms. Significantly higher levels of pro-inflammatory mediators CXCL9, CXCL10, CXCL11, IFNγ and CCL20 in adults, and CXCL9, CXCL10 and CXCL11 in adolescents, were found after vaccination. Participants who showed high innate immune responsiveness had higher odds (OR 6.0; 95 % CI 1.4–33) of experiencing one or more moderate symptoms. No association was found between innate responsiveness or having one or more moderate symptoms with Spike S1- or RBD-antibody concentration at day 28 after vaccination. Conclusion Our results suggest an association between the strength of the innate immune response and the severity of reactogenicity to SARS-CoV-2 vaccination. However, more research is needed to understand the relation between reactogenicity and immunogenicity of COVID-19 vaccines.