Heterologous vaccine regimens against COVID-19
Authors: Talita Duarte-Salles, Daniel Prieto-Alhambra
Journal: The Lancet (2021)

The rapid development of vaccines against COVID-19 is the biggest achievement of science in the fight against the pandemic. Although the efficacy and safety of all approved vaccines have been demonstrated in large clinical trials, recent safety signals have been reported,1European Medicines AgencyAstraZeneca's COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets.https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-bloodDate: April 7, 2021Date accessed: June 16, 2021Google Scholar, 2European Medicines AgencyCOVID-19 vaccines: update on ongoing evaluation of myocarditis and pericarditis.https://www.ema.europa.eu/en/news/covid-19-vaccines-update-ongoing-evaluation-myocarditis-pericarditisDate: June 11, 2021Date accessed: June 16, 2021Google Scholar highlighting the importance of post-marketing surveillance with study populations larger than those of the trials, and representative of populations receiving vaccines as part of routine clinical practice. Safety concerns regarding the ChAdOx1-S vaccine have led some European countries (eg, Denmark) to minimise its use, with other countries recommending the switch from the trial-tested homologous booster to a heterologous booster, such as with BNT162b2.3European Centre for Disease Prevention and ControlOverview of EU/EEA country recommendations on COVID-19 vaccination with Vaxzevria, and a scoping review of evidence to guide decision-making. 18 May 2021. European Centre for Disease Prevention and Control, Stockholm2021Google Scholar This recommendation has come as a surprise to some, because abundant data on more than 9 million people suggested a much reduced risk of thrombotic events with the second dose of ChAdOx1-S.4Medicines and Healthcare products Regulatory AgencyCoronavirus vaccine—weekly summary of Yellow Card reporting.https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions/coronavirus-vaccine-summary-of-yellow-card-reportingDate: June 10, 2021Date accessed: June 16, 2021Google Scholar In contrast, the evidence for the effectiveness and safety of heterologous vaccination regimens remains limited, and based on small phase 2 trials and cohort studies including fewer than 500 participants.5Shaw RH Stuart A Greenland M et al.Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data.Lancet. 2021; 397: 2043-2046Summary Full Text Full Text PDF PubMed Scopus (196) Google Scholar, 6Schmidt T Klemis V Schub D et al.Immunogenicity and reactogenicity of a heterologous COVID-19 prime-boost vaccination compared with homologous vaccine regimens.medRxiv. 2021; (published online June 15.) (preprint).https://doi.org/10.1101/2021.06.13.21258859Google Scholar In The Lancet, Alberto Borobia and colleagues7Borobia AM Carcas AJ Pérez-Olmeda M et al.Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.Lancet. 2021; (published online June 25.)https://doi.org/10.1016/S0140-6736(21)01420-3Summary Full Text Full Text PDF PubMed Scopus (286) Google Scholar report the first results of a phase 2 trial in five university hospitals across Spain assessing the immunogenicity and reactogenicity of the BNT162b2 vaccine administered as second dose in people primed with ChAdOx1-S. The study included 676 adults aged 18–60 years (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men) followed up for 14 days, and showed that BNT162b2, given as a second dose 8–12 weeks after a first dose of ChAdOx1-S, induced a robust immune response and mild reactogenicity. This trial compared this heterologous vaccine regimen to no booster vaccination, and the lack of a homologous vaccination comparator is a limitation of the study,8Comunicado de 17 Sociedades Científicas sobre las vacunas para la COVID-19.https://www.actasanitaria.com/wp-content/uploads/2021/04/Comunicado-Vacunas-SSCC-VF.pdfDate: April 30, 2021Date accessed: June 18, 2021Google Scholar because it does not allow for a direct comparison of the vaccination schedules used in current clinical practice. As in most phase 2 trials, the study has limited representativeness with strict eligibility criteria, including the exclusion of vulnerable and elderly people. This decision is in discord with the global prioritisation of these groups for vaccination. The high immunogenicity reported by Borobia and colleagues is promising, with 100% of participants exhibiting neutralising antibodies 14 days after BNT162b2 administration. Heterologous schedules are of interest for numerous reasons, including logistical considerations and clinical efficacy. The approval of heterologous vaccination will be an opportunity to make vaccination programmes more flexible in response to fluctuations in supply, which is of particular importance for countries with scarce vaccine access and in countries where different vaccines might become available at different times.9Mathieu E Ritchie H Ortiz-Ospina E et al.A global database of COVID-19 vaccinations.Nat Hum Behav. 2021; (published online May 10.)https://doi.org/10.1038/s41562-021-01122-8PubMed Google Scholar Heterologous regimens also have the potential to produce a stronger response,10Spence AJ McKay PF Belij-Rammerstorfer S et al.Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice.Nat Commun. 2021; 122893Crossref PubMed Scopus (86) Google Scholar therefore leading to higher efficacy. Finally, it is predicted that mixing vaccines will be necessary with the appearance of new SARS-CoV-2 variants. Beyond efficacy, safety has been stated to be a key motivator for the use of heterologous vaccination regimens in people primed with ChAdOx1S. However, most of the adverse events listed by regulatory agencies in safety surveillance of COVID-19 vaccines are extremely rare.11Li X Ostropolets A Makadia R et al.Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study.BMJ. 2021; 373n1435Crossref Scopus (103) Google Scholar These events can only be detected in ongoing studies including hundreds of thousands, or millions, of people. The small sample size and short follow-up of the study by Borobia and colleagues did not allow for a full assessment of the safety of the proposed heterologous vaccination regimens. Additionally, the reported reactogenicity in the study by Borobia and colleagues is not in line with a previous active comparator, randomised controlled trial, where 114 participants who were randomly assigned to the proposed heterologous vaccination regimen had many more, and more intense, short-term adverse events than the participants who received the homologous regimen.11Li X Ostropolets A Makadia R et al.Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study.BMJ. 2021; 373n1435Crossref Scopus (103) Google Scholar More research is needed on the correlation between reactogenicity and severe (albeit extremely rare) adverse effects, and the reasons these two trials show such different results. In conclusion, heterologous vaccination regimens against COVID-19 provide an opportunity to speed up vaccination campaigns worldwide, maximising their impact on the control of the pandemic. This study is the first report of a randomised controlled trial testing heterologous vaccination, and should be the basis for future studies. Large phase 3 trials including homologous vaccination as a comparator and further observational studies are urgently needed to inform the clinical effectiveness and safety of heterologous regimens in the target populations and settings. TD-S declares no competing interests. DP-A's research group has received research grants from the European Medicines Agency, the Innovative Medicines Initiative, Amgen, Chiesi, and UCB Biopharma; and consultancy or speaker fees from Astellas, Amgen, AstraZeneca, and UCB Biopharma, all outside of the area of work commented on here. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trialBNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile. Full-Text PDF