Tolerability of MenACWY-TT Vaccination in Toddlers in the Netherlands; A Questionnaire Study


 Background: In May 2018, the monovalent MenC-TT conjugate vaccine given at 14 months of age within the National Immunization Programme in the Netherlands was replaced by a 4-valent MenACWY-TT conjugate vaccine. Methods: Results from a questionnaire about local reactions and systemic events within 4 days after vaccination were compared with data from a comparable tolerability study of a monovalent MenC-TT vaccine. Results: The response rate was 5.5% (1157/20966 questionnaires). Any local reaction was reported for 3.7% of the toddlers, with the highest percentage found for local redness at the injection site (2.9%). Any systemic event was reported for 32.4% of the toddlers, with listlessness (22.4%) most often reported. Fever was the only symptom more frequently reported after MenACWY-TT vaccination compared with MenC-TT vaccination (adj OR 1.61; 95% CI 1.29-2.01).Conclusions: the 4-valent MenACWY-TT vaccine showed to be a little more reactogenic compared with to the monovalent MenC-TT vaccine, with a higher risk of fever within 4 days after vaccination. For the other factors no increased risks were found. Overall, this study shows that MenACWY-TT vaccination is well tolerated in toddlers.

Four days after the scheduled vaccination date, the parents received an email invitation to access the rst questionnaire with their account on the website. This questionnaire asked about symptoms observed within four days after immunization (local reactions and systemic events). The invitation to ll in the second and third questionnaire was sent 14 and 28 days after the vaccination date, respectively. These questionnaires collected additional data on AEs not recovered after lling in the rst questionnaire, and about systemic events related to the MMR vaccination. Results from these questionnaires will be reported separately.
A reminder was sent 2 days after the rst questionnaire and 5 days after the second and third questionnaire.

Questionnaire
The questionnaire included questions about the onset of local reactions and systemic events within four days after vaccination. Local reactions included swelling, redness, blue, induration, warmth, itch and pain at the injection site. Systemic events addressed sleeping problems, fever, being listless/apathetic, decreased appetite, vomiting, diarrhea, somnolence, rash, and other complaints. The presence was dichotomized (yes/no).
Information about the course of each symptom was also collected: time to onset, outcome, duration and impact (see Table 2 and Table 3 for grading scales). Additionally, the use of analgesics, occurrence of medical intervention, absence from childcare and/or other activities, and parents' or guardians' absence from work were asked.
Background information was collected regarding gender, medical history (i.e. positive when child regularly suffers from one or more of the following: coughing/shortness of breath, vomiting and/or diarrhea, infections, rash, hypersensitivity/allergy, other), number of children in household and attending daycare.

Statistical analysis
Assuming a percentage of fever of 8.2% (95% CI 6.7-10.1) in children participating in the MenC-TT study of Lareb, a 95% con dence level and a width of the con dence interval of 5%, the sample size should be 1239 adolescents to be able to detect an absolute elevated risk of 1.5% (18). Assuming a response rate of 10% and a drop-out rate of 40%, about 20600 parents were needed to be invited for participation.
Differences in baseline characteristics between the two study groups were calculated using the Chi-square test and Mann-Whitney U test. The percentage of infants experiencing AEs within 4 days after immunization and 95% CIs were computed by type and severity of the AE. Binary logistic regression analysis was used to calculate odds ratios (ORs) for the relationship between local reactions and systemic AEs (dependent variables) and type of vaccine (independent variable) adjusted for gender, medical history, number of children in household, attending daycare. Proportions of absence from child-care and/or other activities, parents' absence from work, and medical intervention within 4 days after vaccination were calculated with their 95% CIs.
Analyses were performed using SPPS statistics 24.

Response rate and population characteristics
In total, 20966 invitations letters were sent to parents from children who were eligible for the MenACWY-TT vaccination.
Of these, 1500 agreed to participate (7,2%). The response rate for the questionnaire on symptoms within 4 days after vaccination was 5.5% (n = 1157) and a little lower than the response rate in the comparative MenC-TT study of Lareb (6.4% (n = 2727).
Of all respondents, 50.1% concerned male toddlers (see Table 1). In the MenACWY-TT study 76.9% of the children attended daycare, which is more than in the previous MenC-TT study (60.3%; p < 0.01). In the MenACWY-TT study, a medical history was reported for 39% of the toddlers, with coughing/shortness of breath (17.9%) and rash (16.1%) as most reported. In the MenC-TT study, these comorbidities were less frequent (29.2%), also with rash (11,4%) and coughing/shortness of breath (11.0%) most frequently reported. Furthermore, the distribution in season of vaccination was signi cantly different between the two groups (p < 0.01). Local reactions after MenACWY-TT vaccination Table 2 shows the frequency, severity, onset time and duration of local reactions that occurred within 4 days after vaccination. Within these period, parents reported one or more local reactions in 43 children (3.7 %) with a total of 103 local reactions reported. Injection site redness was the most commonly reported local reaction. Most of the reactions were recovering or had already recovered within 4 days after vaccination (88.3%). The mean time of onset of the different local reactions was within 17 hours after vaccination and ranged from 0-72 hours. The mean duration was 32.3 hours (range 0-72 hours). None of the parents reported that local reactions had high impact. Parents from children with a medical history reported signi cantly more often vomiting after vaccination than children without a medical history (OR 2.24, 95% CI 1. 15-4.38). No other signi cant associations between adverse events and medical history were found.

Absence and medical intervention after MenACWY-TT vaccination
Absence from attending childcare within 4 days after vaccination was reported in 10.2% of the children. The median duration was 1-2 days (see Table 4).
From all parents or guardians, 5.5% were absent from work to take care of the vaccinated child, with a median of also 1-2 days. Analgesics within 4 days after vaccination were used by 18.1% of the children. Almost all of them used paracetamol to treat fever and the median duration was less than 1 day (see Table 4). For eight children, the general practitioner or youth doctor was called for medical advice, and another twelve children visited the GP or youth doctor for their AEs. Main reasons for contacting the GP were fever (n = 7; including one child with febrile convulsions, local reactions (n = 2), extensive crying (n = 2) and anxiousness of the parents (n = 2).

Comparison AEs after MenACWY-TT vs. MenC-TT vaccination
Fever was the only symptom with a higher risk after MenACWY-TT vaccination compared to MenC-TT vaccination (adj OR 1.61; 95%CI 1.29-2.01) (see Table 5). For local reactions as well as for the other systemic events, no increased risks were found after MenACWY-TT vaccination.

Discussion
In the present study we evaluated the tolerability of the newly introduced MenACWY-TT vaccine in the NIP in toddlers. Our results show that solicited systemic AEs like listlessness, fever and sleeping problems frequently occur, although most of them recovered within 4 days. The frequency of rash was much lower, but the majority of the children had not recovered after 4 days. However, rashes are also a known adverse event of MMR vaccination which usually occurs 5-21 days after vaccination. Therefore, overlapping frequencies of this adverse event from both vaccines may explain the longer duration. A follow-up questionnaire showed that only 2 children experiencing rash within 4 days after vaccination, did not recover within 30 days after vaccination (data not shown). The impact for most of the systemic AEs was mild to moderate, but parents reported on a high impact of sleeping problems and the vomiting, while hardly mentioning problems with local reactions.
The tolerability of MenACWY-TT observed in our study was in line with that observed in Lareb's MenC-TT study conducted a few years earlier in a similar group of young children in the Netherlands. Only for fever a higher risk after MenACWY-TT vaccination was found within 4 days after vaccination.
The frequencies of local reactions we found in our study are remarkable lower compared with the results from post-licensure trials. In our study, redness was the most reported local reaction (2.9%), whereas in other studies percentages up to 45% were found for local reactions (10,12,(19)(20)(21). In the clinical trials, irritability was one of the most mentioned solicited general symptoms with frequencies between 15 and 45% (10,12,19,20), whereas in our study, listlessness was the most reported systemic AE (22.4%). Unfortunately, we did not include irritability in our questionnaire, whereas the trials did not describe listlessness. Drowsiness was another frequently mentioned systemic AE in the trials (15-35%), whereas in our study somnolence was hardly reported (2.7%). On the other hand, the results for loss of appetite (10.5% in our study vs. 10-25% in the trials) and fever (13.4% vs. 5-30%) were more consistent. Differences in study design (cross-section vs RCTs, data collection, age distribution) may contribute to the differences in our results and the results from clinical trials. This is underlined by the fact that our results are very similar to the results of Lareb's MenC-TT study, which had the same study design. Only for fever a signi cant difference was found between these studies There were a few number of limitations to this study. Compared to Lareb's MenC-TT study, signi cant differences were identi ed in baseline characteristics for comorbidity, attending daycare and seasonality. Although this may in uence the frequency of for example fever, no different risk estimations were found between the adjusted and unadjusted analyses. Confounding by any of the covariates is therefore unlikely.
Data from the MenACWY-TT and Lareb's MenC-TT study were collected in different years. As the circulation of infectious agents differs between years, this may have in uenced the frequency of some systemic events, like fever, diarrhea and vomiting. Since many of these events in our study recovered within 4 days, we assume that this effect is limited. However, the actual effect is unknown.
The non-response in both studies was high. A low response rate can give rise to sampling bias if the nonresponse is unequal among the participants regarding exposure and/or outcome. It is not clear to what extent this has occurred in this study. But since they have the same study design, it may be assumed that the reasons for non-response is similar for the MenACWY-TT and MenC-TT study. Therefore it is unlikely that the comparison of these studies is biased.

Conclusions
This questionnaire-based study shows, in line with pre-licensure data, that MenACWY-TT vaccination has a good tolerability. Local reactions hardly occur. Most reported systemic AEs are listlessness, fever and sleeping problems. Most of the events were mild to moderate and transient but the impact of sleeping problems and vomiting was relatively high. The MenACWY-TT vaccine showed to be a little more reactogenic compared to the MenC-TT vaccine, expressed by a higher risk of fever within 4 days after vaccination. For the other factors no increased risks were found. Overall, our study shows that MenACWY-TT vaccination is well tolerated in toddlers. Written informed consent was obtained from all adolescents included in the study and their parents.

Consent for publication
Not applicable Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.