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Heterologous booster COVID-19 vaccination

Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands An agency of the European Union Address for visits and deliveries Refer to Send us a question Go to Telephone +31 (0)88 781 6000 European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. 13 December 2021 EMA/349565/2021 Biological Health Threats and Vaccine Strategy Office EMA Pandemic Task Force for COVID-19 (COVID-ETF) Heterologous primary and booster COVID-19 vaccination Evidence based regulatory considerations the spring of 20211, a number of European Union (EU) Member States (MSs) started to apply a strategy of Heterologous primary vaccination , with at least 11 EU MSs vaccinating with a first dose of Vaxzevria followed by a second dose of Comirnaty due to uncertainties related to the risk of Thrombosis with thrombocytopenia syndrome (TTS) following Vaxzevria.

Heterologous primary and booster COVID-19 vaccination Evidence based regulatory considerations 1. Introduction During the spring of 20211, a number of European Union (EU) Member States (MSs) started to apply a strategy of heterologous primary vaccination, with at least 11 EU MSs vaccinating with a first dose of

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Transcription of Heterologous booster COVID-19 vaccination

1 Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands An agency of the European Union Address for visits and deliveries Refer to Send us a question Go to Telephone +31 (0)88 781 6000 European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. 13 December 2021 EMA/349565/2021 Biological Health Threats and Vaccine Strategy Office EMA Pandemic Task Force for COVID-19 (COVID-ETF) Heterologous primary and booster COVID-19 vaccination Evidence based regulatory considerations the spring of 20211, a number of European Union (EU) Member States (MSs) started to apply a strategy of Heterologous primary vaccination , with at least 11 EU MSs vaccinating with a first dose of Vaxzevria followed by a second dose of Comirnaty due to uncertainties related to the risk of Thrombosis with thrombocytopenia syndrome (TTS) following Vaxzevria.

2 This decision by public health authorities was based on preliminary results from independently conducted observational studies and clinical trials. Moreover, a Heterologous vaccination strategy has historically been applied for other vaccines 2. Nevertheless this measure raised questions linked to the quality and amount of data underpinning the decision. The focus has subsequently expanded to understand the benefits and risks of a Heterologous boosting regimens, in which the primary vaccination series consisting of 1 or 2 doses (one dose was studied and authorised only for the Janssen COVID-19 vaccine) is followed by a third dose given at least 3 to 6 months later with a different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. Understanding the efficacy, durability of protection and safety of Heterologous primary and booster regimens against SARS-CoV-2 is important to support alternative vaccination strategies and programmatic flexibility amid supply delays and safety concerns that have slowed vaccination campaigns.

3 Moreover, emerging evidence indicates that Heterologous primary or booster vaccination could improve the immune response as compared to homologous vaccination , at least with certain combinations. Results support consideration of strategies for maximising the level of protection that can be obtained. This document includes a summary and appraisal of the available evidence from clinical studies and real world evidence to support the use of Heterologous vaccination against Coronavirus Disease ( COVID-19 ) within primary series and/or for booster doses. The option of Heterologous vaccination is not yet reflected in the product information of authorised vaccines. Marketing authorisation holders are encouraged to submit variations to add details about such use to the product information.

4 1 2 Shan Lu. Heterologous prime boost vaccination . Curr Opin Immunol 2009; 21: 346-51 Heterologous primary and booster COVID-19 vaccination EMA/349565/2021 Page 2/26 Although the review did not look at vaccines not yet licensed in the EU, research into Heterologous combinations of these will be taken into account in future if these are licensed. The screening of the scientific literature was not based on formal systematic criteria and the cut-off date for data collection was 3 December 2021. Studies with less than 10 participants were not included. Vaxzevria, Comirnaty, SpikeVax, Janssen COVID-19 vaccine, Curevac s mRNA vaccine, Novavax vaccine, Valneva s vaccine and CoronaVac are called respectively AZ, BNT, Moderna, JJ, CVn, NVX, VLA and CV throughout this document. This document was adopted by the EMA Pandemic Task Force for COVID-19 (COVID-ETF) on 14 December 2021.

5 2. Summary of evidence on Heterologous primary vaccination Main studies on immunogenicity and safety The Com-COV clinical trial is a multi-centre, participant-masked, randomised non-inferiority trial where all four prime-boost permutations of the AZ and BNT vaccines both at 28-day and 84-day prime-boost intervals were compared in 830 individuals 50-69 years of age. In the initial manuscript published by Shaw R. et only reactogenicity data were presented consisting of self-reported solicited local and systemic symptoms collected in the 7 days after each dose in participants randomised to receive vaccines at 28-day intervals. Overall greater systemic reactogenicity was seen after the Heterologous boost dose than their homologous boost counterparts. Among the most common adverse events (AEs), feverishness was reported by 24% more people (95% Confidence Interval (CI) 13 35%) after the AZ+BNT schedule, and by 20% more people after the BNT+AZ schedule as compared to their homologous counterparts, and this was accompanied by increased paracetamol usage (about 20% increase).

6 Similar increases were observed for chills, fatigue, headache, joint pain, malaise, and muscle ache, and were mostly seen in the 48 hours post immunisation but all reactogenicity symptoms were short lived and no AEs led to hospitalizations. Of note, the reported analyses are descriptive, as the study was not powered for reactogenicity. No concerns arose from the limited haematology and biochemistry data available, which showed similar profiles between Heterologous and homologous vaccine schedules. In a second publication from the Com-COV trial, Liu et al. 4 reported the safety and immunogenicity of AZ and BNT vaccine schedules in the 28-day boost study groups. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike Immunoglobulin G (IgG) concentration at 28 days after boost, when comparing AZ/BNT with AZ/AZ, and BNT/AZ with BNT/BNT in participants who were seronegative for SARS-CoV-2 infection at baseline.

7 Immunological secondary outcomes included anti-spike binding IgG concentration, cellular responses measured by Interferon gamma (IFN ) ELISpot in peripheral blood, and pseudotype virus neutralisation titres at days 0, 28, and 56. Of the 830 subjects enrolled, a small subset (n=100) were enrolled into an immunology cohort, who had four additional blood tests to evaluate antibody kinetics further; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). 3 Robert H Shaw et al. Heterologous prime-boost COVID-19 vaccination : initial reactogenicity data The Lancet, May 2021 (21)01115-6/fulltext 4 Liu et al., Safety and immunogenicity of Heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial Heterologous primary and booster COVID-19 vaccination EMA/349565/2021 Page 3/26 Binding IgGs were measured by a standardized ELISA, and reported as ELISA Laboratory Unit (ELU)/ml; 50% neutralising antibody titre (NT50) were measured by a qualified pseudotype virus neutralisation assay (PNA), using a vesicular stomatitis virus backbone, and by a live SARS-CoV-2 virus microneutralization assay (for a limited set of samples).

8 The results were not presented in the assigned unit as per WHO International Standards (IS) ( international units (IU)/ml for neutralizing antibodies and binding antibody units (BAU)/ml for IgG) but the correlation factors for the conversion were provided (for the assays: PNA, receptor binding domain (RBD) ELISA and Pre-Spike IgG ELISA). The Heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97 5% CI of the GMR of serum SARS-CoV-2 anti-spike IgG concentration at 28 days after boost was greater than 0 63. The study was powered to 90% at a one-sided 2,5% significance level. The results showed that the geometric mean concentration (GMC) of SARS-CoV-2 anti-spike IgG at day 28 post-boost for recipients of both Heterologous schedules (AZ+BNT and BNT+AZ) were higher than the GMC of the homologous AZ vaccine schedule, however only the AZ+BNT demonstrated non-inferiority to the homologous AZ+AZ schedule (12,906 ELU/mL vs.)

9 1392 ELU/mL, with a GMR of 9 2 (one-sided 97 5% CI 7 5 to ). BNT/AZ (7133 ELU/mL) failed to meet NI against the homologous schedule (BNT/BNT, 14080 ELU/mL). Exploratory analyses on T cell responses showed that their geometric mean at 28 days post boost was highest when subjects received the Heterologous schedule AZ+ BNT. Regarding safety within 28 days post-boost, no significant difference was observed between the vaccine schedules in the proportion of participants with at least one adverse event. The total number of AEs was higher for the BNT/BNT and BNT/AZ schedules (81 and 90 respectively vs. 74 and 71 for the AZ/AZ and AZ/BNT). However the proportion of AEs of grade 3 severity was highest for the AZ/BNT schedule ( AZ/AZ and AZ/BNT vs. BNT/BNT and BNT/AZ). Based on unpublished data, when administering the second dose with a 12 weeks interval, less reactogenicity was reported for AZ/BNT combo as compared to the same schedule with 28 days interval.

10 Regarding immunogenicity, the prolonged schedule increased immunogenicity further for AZ/BNT combo as compared to the homologous AZ/AZ schedule, while BNT/BNT was still superior to BNT/AZ, although the latter difference was much less pronounced than after the 4 weeks interval. Supportive studies on immunogenicity and safety EICOV and COVIM5 are prospective cohort studies conducted by the Berlin Institute of Health and Charit to assess reactogenicity and immunogenicity of Heterologous immunisation in 380 health care workers (median age 35 years) who were offered AZ prime followed by BNT boost 10-12 weeks later (COVIM study) compared with homologous AZ vaccination with a similar interval, or homologous BNT/BNT with a 3-week interval (EICOV study). Blood samples for detection of SARS-CoV-2-specific antibodies and T-cell responses were collected immediately before the first vaccination , and 3 4 weeks after the first and second vaccination .


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