Optimising SARS-CoV-2 vaccination schedules
Authors: Cristobal Belda-Iniesta
Journal: The Lancet (2021)

The objective of any vaccination strategy is to achieve long-term protection against infection and also to reduce the mortality and morbidity associated with the eventual development of disease. This dual perspective usually requires repeated immunisations. Several factors affect the immunological outcome of repeated immunisations, such as the antigen selected, the time between doses, and the type of vector.1Palgen J-L Feraoun Y Dzangué-Tchoupou G et al.Optimize prime/boost vaccine strategies: trained immunity as a new player in the game.Front Immunol. 2021; 12: 554Crossref Scopus (67) Google Scholar Once the initial vaccination schedules have been approved, trials must be designed to optimise immunological outcomes by adjusting these parameters and others. In The Lancet, Xinxue Liu and colleagues2Liu X Shaw RH Stuart ASV 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.Lancet. 2021; (published online Aug 6.)https://doi.org/10.1016/S0140-6736(21)01694-9Summary Full Text Full Text PDF Scopus (359) Google Scholar present results for four of the eight intervention groups of the Com-COV clinical trial, showing that the immunological response of double-dose ChAdOx1 nCoV-19 (AstraZeneca; hereafter referred to as ChAd) is statistically lower than any other schedule including BNT162b2 (Pfizer–BioNTech, hereafter referred to as BNT) and ChAd at 28 days post boost dose, with a 28-day prime–boost interval. In addition, their findings support previous published data from an academic study done by the Instituto de Salud Carlos III, of which I was an investigator and author,3Borobia AM Carcas AJ Pérez-Olmeda M Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.Lancet. 2021; 398: 121-130Summary Full Text Full Text PDF PubMed Scopus (287) Google Scholar suggesting that a heterologous schedule based on the sequential administration of ChAd and BNT could be highly immunogenic, and perhaps more immunogenic than homologous schedules based on ChAd. In addition, Liu and colleagues show that double-dose BNT is more potent in inducing a humoral response than the BNT–ChAd permutation. The SARS-CoV-2 humoral immune response has been used in early clinical trials as a surrogate marker of protection.4Folegatti PM Ewer KJ Aley PK et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.Lancet. 2020; 396: 467-478Summary Full Text Full Text PDF PubMed Scopus (1774) Google Scholar, 5Mulligan MJ Lyke KE Kitchin N et al.Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults.Nature. 2020; 586: 589-593Crossref PubMed Scopus (1062) Google Scholar, 6Jackson LA Anderson EJ Rouphael NG et al.An mRNA vaccine against SARS-CoV-2—preliminary report.N Engl J Med. 2020; 383: 1920-1931Crossref PubMed Scopus (2303) Google Scholar However, the minimum titre of SARS-CoV-2 protein S neutralising antibodies to induce protection is unknown. We do not even know if this minimum titre exists in clinical practice. In this regard, Liu and colleagues appropriately contextualise their immunological findings with the evidence of protection against hospitalisation and severe disease from phase 3 trials using homologous schedules.7Voysey M Costa Clemens SA Madhi SA et al.Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.Lancet. 2021; 397: 881-891Summary Full Text Full Text PDF PubMed Scopus (806) Google Scholar The clinical and epidemiological relevance of these immunological differences will be inferred when information about morbidity induced by re-exposure to SARS-CoV-2 in vaccinated populations becomes available. The authors observed no differences in safety between the four study groups, although reactivity was higher in the heterologous schedules.8Shaw RH Stuart A Greenland M Liu X Van-Tam JSN Snape MD Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data.Lancet. 2021; 397: 2043-2046Summary Full Text Full Text PDF PubMed Scopus (198) Google Scholar In this respect, the comparative safety and reactogenicity between the four groups deserve special consideration because the study was designed as a non-inferiority trial. Non-inferiority trials are randomised studies in which authors focus on whether an experimental arm is not clinically and statistically inferior to an active control group.9D'Agostino RB Massaro JM Sullivan LM Non-inferiority trials: design concepts and issues—the encounters of academic consultants in statistics.Stat Med. 2003; 22: 169-186Crossref PubMed Scopus (563) Google Scholar Therefore, when an experimental scheme meets with the non-inferiority criteria for efficacy, the differences in safety between the compared schemes should guide the clinical impact analysis. Additionally, authors included a preplanned definition of superiority that allowed for a switch from non-inferiority to superiority. From a statistical perspective, this demonstration is valid on its own, as long as safety profiles of the compared schedules are similar. If the safety profiles were different, the authors would need to estimate the size effect to assess whether it is sufficient to outweigh the adverse effects. In the Com-COV trial, safety is similar between groups but reactogenicity was higher in the heterologous schedules.8Shaw RH Stuart A Greenland M Liu X Van-Tam JSN Snape MD Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data.Lancet. 2021; 397: 2043-2046Summary Full Text Full Text PDF PubMed Scopus (198) Google Scholar It is clear that reactogenicity, although more intense in this study, is of little clinical relevance and could be modulated by modifying the time between doses.4Folegatti PM Ewer KJ Aley PK et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.Lancet. 2020; 396: 467-478Summary Full Text Full Text PDF PubMed Scopus (1774) Google Scholar Therefore, vaccination policy makers should estimate the size effect of the immunological humoral response to assess whether it is sufficient to compensate for the reactogenicity events. The Com-COV trial, like the CombiVacS trial,3Borobia AM Carcas AJ Pérez-Olmeda M Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.Lancet. 2021; 398: 121-130Summary Full Text Full Text PDF PubMed Scopus (287) Google Scholar was not able to identify very low-frequency adverse events. Of course, no phase 2 study is able to do so. However, some phase 3 clinical trials have not been sufficiently powered to identify very low-frequency events, such as those that have provoked the controversy over the use of ChAd.10European Medicines AgencyCOVID-19 vaccine safety update: Vaxzevria, AstraZeneca.https://www.ema.europa.eu/documents/covid-19-vaccine-safety-update/covid-19-vaccine-safety-update-vaxzevria-previously-covid-19-vaccine-astrazeneca-14-july-2021_en.pdfDate: July 14, 2021Date accessed: July 22, 2021Google Scholar Therefore, any approach to identify this type of event must be oriented towards a good use of pharmacovigilance programmes or phase 4 clinical trials. Liu and colleagues reported similar types, frequency, and intensity of events to those detected with the individual use of each of the vaccines. In summary, the question to be answered is whether the data published by Liu and colleagues, in combination with those previously published by Borobia and colleagues,3Borobia AM Carcas AJ Pérez-Olmeda M Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.Lancet. 2021; 398: 121-130Summary Full Text Full Text PDF PubMed Scopus (287) Google Scholar are enough evidence to initiate the modification of vaccination schedules. Alternatively, large academic phase 3 clinical trials could explore the protection against severe disease, intensive care unit admission, and SARS-CoV-2 mortality using heterologous schedules, but the time and effort that this work would entail should be carefully balanced against the potential benefits. I am the study chair of the CombiVacS clinical trial and the deputy general manager of the Instituto de Salud Carlos III. 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 trialDespite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. Full-Text PDF