Effect of Different SARS-CoV-2 Vaccine Schedules and Vaccination Intervals on Reactogenicity and Humoral Immunogenicity

Study Overview
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Brief Summary
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Investigation of the reactogenicity and immunogenicity of homologous and heterologous vaccine combinations with regard to the formation of SARS-CoV-2 antispike antibodies in health care workers after basic immunization and boost vaccination

Detailed Description
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The basic immunizations (first and second vaccination) were performed from January to June 2021 using the m-RNA vaccine BNT162b2 (BioNTech/Pfizer, B)9 and the vector-based vaccine ChAdOx1-S (AstraZeneca, A). BNT162b2 was used to boost vaccine all study population. The time interval between the basic immunisation and the boost vaccination varied. Four vaccine-groups could be distinguished: Group 1 received BNT162b2 with the second vaccination 3 weeks after the first vaccination. Vaccinees of groups 2 and 3 received AZD1222/ChAdOx1-S as first vaccination and could choose after 12 weeks whether second vaccination with BNT162b2 or AZD1222/ChAdOx1-S should be carried out. This results in homologous (first: AZD1222/ChAdOx1-S, second: AZD1222/ChAdOx1-S) and heterologous (first: AZD1222/ChAdOx1-S, second: BNT162b2) vaccine combinations. Group 4 received BNT162b2 with the second vaccination 6 weeks after first vaccination. Blood samples were collected at six time points: four weeks, three and six months after completion of the basic immunization, immediately before boost vaccination, four weeks and three months after boost vaccination. Reactogenicity after first, second, and boost vaccination was assessed using questionnaires to determine vaccine-induced adverse drug reactions (ADR) within seven days after the respective vaccinations. In addition, demographic data (age, gender, occupational group, allergies) were collected, local and systemic vaccination reactions are differentiated and the need for medication and inability to work as a result of vaccination reactions are prospectively recorded.

Official Title
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Comparison of Different BNT162b2 and ChAdOx1-S COVID-19 Vaccination Intervals and Combinations on Reactogenicity and Humoral Immunogenicity in Adults

Conditions
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SARS-CoV2 Infection, Immunisation Reaction, Antibody Hypersensitivity, Tolerance

Intervention / Treatment
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* Drug: IM injection of vaccination (mRNA vaccination)
* Drug: IM injection of vaccination (vector based vaccination)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: hospital staff who received COVID-19 vaccination Exclusion Criteria: lack of a written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| BNT162b2/BNT162b2 - 3 wks<br>hospital staff receiving BioNTech as prime vaccination and also receiving BioNTech after 3 weeks as boost vaccination | Drug: IM injection of vaccination (mRNA vaccination)<br>* mRNA vaccination<br>* Other names: Cormirnaty (BioNTech/Pfizer);|
| ChAdOx1/ChAdOx1 - 12 wks<br>hospital staff receiving AstraZeneca as prime vaccination and also receiving AstraZeneca as boost vaccination after 12 weeks | Drug: IM injection of vaccination (vector based vaccination)<br>* vector based vaccination<br>* Other names: AZD1222 (AstraZeneca);|
| ChAdOx1/BNT162b2 - 12 wks<br>hospital staff receiving AstraZeneca as prime vaccination and receiving BioNTech as boost vaccination after 12 weeks | Drug: IM injection of vaccination (mRNA vaccination)<br>* mRNA vaccination<br>* Other names: Cormirnaty (BioNTech/Pfizer);Drug: IM injection of vaccination (vector based vaccination)<br>* vector based vaccination<br>* Other names: AZD1222 (AstraZeneca);|
| BNT162b2/BNT162b2 - 6 wks<br>hospital staff receiving BioNTech as prime vaccination and also receiving BioNTech after 6 weeks as boost vaccination | Drug: IM injection of vaccination (mRNA vaccination)<br>* mRNA vaccination<br>* Other names: Cormirnaty (BioNTech/Pfizer);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference between the four cohorts regarding the antibody of the viral spike protein 4 weeks after second vaccination | The descriptive data are described by frequencies (%/n) and the continuous data by corresponding position parameters (median, interquartile range). The confirmatory analysis is performed using the Wilcoxon or Kruskal-Wallis test. The Bonferroni correction is applied accordingly. | 4 weeks after second vaccination | 
| Difference between the four cohorts regarding the antibody of the viral spike protein 3 months after second vaccination | The descriptive data are described by frequencies (%/n) and the continuous data by corresponding position parameters (median, interquartile range). The confirmatory analysis is performed using the Wilcoxon or Kruskal-Wallis test. The Bonferroni correction is applied accordingly. | 3 months after second vaccination | 
| Difference between the four cohorts regarding the antibody of the viral spike protein 6 months after second vaccination | The descriptive data are described by frequencies (%/n) and the continuous data by corresponding position parameters (median, interquartile range). The confirmatory analysis is performed using the Wilcoxon or Kruskal-Wallis test. The Bonferroni correction is applied accordingly. | 6 months after second vaccination | 
| Difference between the four cohorts regarding the antibody of the viral spike protein directly before boost vaccination | The descriptive data are described by frequencies (%/n) and the continuous data by corresponding position parameters (median, interquartile range). The confirmatory analysis is performed using the Wilcoxon or Kruskal-Wallis test. The Bonferroni correction is applied accordingly. | directly before boost vaccination | 
| Difference between the four cohorts regarding the antibody of the viral spike protein 4 weeks after boost vaccination | The descriptive data are described by frequencies (%/n) and the continuous data by corresponding position parameters (median, interquartile range). The confirmatory analysis is performed using the Wilcoxon or Kruskal-Wallis test. The Bonferroni correction is applied accordingly. | 4 weeks after boost vaccination | 
| Difference between the four cohorts regarding the antibody of the viral spike protein 3 months after boost vaccination | The descriptive data are described by frequencies (%/n) and the continuous data by corresponding position parameters (median, interquartile range). The confirmatory analysis is performed using the Wilcoxon or Kruskal-Wallis test. The Bonferroni correction is applied accordingly. | 3 months after boost vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Do the four cohorts differ in terms of reactogenicity (systemic and/or local vaccine reactions) after the first vaccination? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Do the four cohorts differ in terms of reactogenicity (systemic and/or local vaccine reactions) after the second vaccination? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Do the four cohorts differ in terms of reactogenicity (systemic and/or local vaccine reactions) after the boost vaccination? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after third (boost) vaccination | 
| Differences between the 4 groups after first vaccination regarding a. the individual local vaccination reactions? b. the individual systemic vaccination reactions? c. the number or percentage of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Differences between the 4 groups after second vaccination regarding a. the individual local vaccination reactions? b. the individual systemic vaccination reactions? c. the number or percentage of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Differences between the 4 groups after boost vaccination regarding a. the individual local vaccination reactions? b. the individual systemic vaccination reactions? c. the number or percentage of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after boost vaccination | 
| Is there a difference between the four cohorts regarding the severity of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Is there a difference between the four cohorts regarding the severity of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Is there a difference between the four cohorts regarding the severity of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after boost vaccination | 
| Do the four cohorts differ with respect to the temporal occurrence of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Do the four cohorts differ with respect to the temporal occurrence of vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Is there a difference between the four cohorts regarding the use of medication due to vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | first and second vaccination | 
| Do the four cohorts differ with regard to the need for a certificate of incapacity for work due to vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Are there differences regarding the job groups and the vaccination week days? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Do the four cohorts differ with regard to the need for a certificate of incapacity for work due to vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Are there differences regarding the job groups and the vaccination week days? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Do the four cohorts differ with regard to the need for a certificate of incapacity for work due to vaccination reactions? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after boost vaccination | 
| Are there differences regarding the job groups and the vaccination week days? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after boost vaccination | 
| Are there differences within the cohorts regarding vaccination reactions in subjects with a known allergy? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Are there differences within the total population regarding vaccination reactions in subjects with a known allergy? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after first vaccination | 
| Are there differences within the cohorts regarding vaccination reactions in subjects with a known allergy? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Are there differences within the total population regarding vaccination reactions in subjects with a known allergy? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | immediately after second vaccination | 
| Is there a correlation within cohorts or within the overall population at four weeks regarding the level of antibody and the a. Extent of vaccine response (local, systemic, local & systemic, none)? b. Gender? c. Age? d. BMI? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. Spearman's correlation is calculated. | 4 weeks after second vaccination | 
| Do the variables listed above have an influence on the level of antibody? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. To investigate a potential influence of the variables, a logistic regression is performed if necessary. | 4 weeks after second vaccination | 
| Is there a correlation within cohorts or within the overall population at 3 months regarding the level of antibody and the a. Extent of vaccine response (local, systemic, local & systemic, none)? b. Gender? c. Age? d. BMI? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. Spearman's correlation is calculated. | 3 months after second vaccination | 
| Do the variables listed above have an influence on the level of antibody? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. To investigate a potential influence of the variables, a logistic regression is performed if necessary. | 3 months after second vaccination | 
| Is there a correlation within cohorts or within the overall population at 6 months regarding the level of antibody and the a. Extent of vaccine response (local, systemic, local & systemic, none)? b. Gender? c. Age? d. BMI? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. Spearman's correlation is calculated. | 6 months after second vaccination | 
| Do the variables listed above have an influence on the level of antibody? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. To investigate a potential influence of the variables, a logistic regression is performed if necessary. | 6 months after second vaccination | 
| Is there a correlation within cohorts or within the overall population directly before the boost regarding the level of antibody and the a. Extent of vaccine response (local, systemic, local & systemic, none)? b. Gender? c. Age? d. BMI? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. | directly before boost vaccination | 
| Do the variables listed above have an influence on the level of antibody? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. | directly before boost vaccination | 
| Is there a correlation within cohorts or within the overall population at 4 weeks after boost regarding the level of antibody and the a. Extent of vaccine response (local, systemic, local & systemic, none)? b. Gender? c. Age? d. BMI? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. | 4 weeks after boost vaccination | 
| Do the variables listed above have an influence on the level of antibody? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. | 4 weeks after boost vaccination | 
| Is there a correlation within cohorts or within the overall population at 3 months after boost regarding the level of antibody and the a. Extent of vaccine response (local, systemic, local & systemic, none)? b. Gender? c. Age? d. BMI? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. | 3 months after boost vaccination | 
| Do the variables listed above have an influence on the level of antibody? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. | 3 months after boost vaccination | 
| Is there a statistically significant or clinically relevant difference between the (drop in) antibodies at three months from baseline within the four cohorts? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | 3 months after second vaccination | 
| Is there a statistically significant or clinically relevant difference between the (drop in) antibodies at six months from baseline within the four cohorts? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | 6 months after second vaccination | 
| Is there a statistically significant or clinically relevant difference between the (drop in) antibodies at three months from baseline between the four cohorts? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | 3 months after second vaccination | 
| Is there a statistically significant or clinically relevant difference between the (drop in) antibodies at six months from baseline between the four cohorts? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | 6 months after second vaccination | 
| Are there any subjects within the study follow-up period who had proven SARS Cov2 infection? (Comparison between groups) | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. The analysis is performed using appropriate tests such as Fisher's exact test, Chi² test, Mann-Whitney U test or Kruskal-Wallis test. | until end of study | 
| Is there a correlation within the overall population between the level of antibody and detected SARS Cov2 infection? | For the secondary endpoints, frequencies (%/n) for categorical data and corresponding measures of location (median, interquartile range) for continuous data are used descriptively. | 3 months and 6 months after second vaccination, directly before boost vaccination and 4 weeks and 3 months after boost vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV2, COVID-19, mRNA vaccination, vector based vaccination, heterlogues vaccination, homologues vaccination, HelCoVac, Helios Hildesheim COVID-19 Vaccination Study