Global emergence of SARS-CoV-2 variants: new foresight needed for improved vaccine efficacy
Authors: Pragya D Yadav, Sanjay Kumar
Journal: The Lancet Infectious Diseases (2021)

Apart from COVID-19-appropriate behaviour, effective vaccine coverage is the single most important intervention needed to control the ongoing SARS-CoV-2 pandemic. Although several vaccines are being used under emergency use authorisation, worldwide vaccination coverage will only be achieved when vaccine availability exceeds vaccine demand. Globally, several prominent institutions, universities, and leading pharmaceutical companies have successfully developed COVID-19 vaccine candidates that have progressed to clinical trials. In The Lancet Infectious Diseases, Peter G Kremsner and colleagues1Kremsner PG Ahuad Guerrero RA Arana-Arri E et al.Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial.Lancet Infect Dis. 2021; (published online Nov 23.)https://doi.org/10.1016/S1473-3099(21)00677-0Summary Full Text Full Text PDF PubMed Scopus (88) Google Scholar report data on the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate from a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial in ten countries in Europe and Latin America (HERALD). Between Dec 11, 2020, and April 12, 2021, 39 680 COVID-19-naive adults (aged ≥18 years) were randomly assigned to receive two doses of either CVnCoV or placebo on days 1 and 29, of whom 39 529 received at least one dose of CVnCoV (n=19 783) or placebo (n=19 746). The primary efficacy endpoint was the occurrence of virologically confirmed COVID-19 of any severity caused by any strain from 15 days after the second dose. Key secondary endpoints were the occurrence of virologically confirmed moderate-to-severe COVID-19 or severe COVID-19. Solicited local and systemic adverse events for 7 days after each dose and unsolicited adverse events for 28 days after each dose were monitored as primary safety outcomes. A total of 228 participants developed COVID-19 of any severity over the course of follow-up, of whom 83 were in the CVnCoV group and 145 were in the placebo group. Vaccine efficacy against symptomatic disease of any severity was 48·2% (95·826% CI 31·0–61·4) and 70·7% (95% CI 42·5–86·1) against moderate-to-severe COVID-19. Sequencing data showed that about 97% of COVID-19 cases were caused by variants of concern (ie, alpha [B.1.1.7], gamma [P.1], or delta [B.1.617.2]), variants of interest (lambda [C.37] or mu [B.1.621]), or variants requiring further monitoring. In the CVnCoV group, the most frequently reported solicited local adverse event was injection site pain and the most frequently reported solicited systemic adverse events were fatigue and headache. The US Food and Drug Administration issued emergency use authorisation for two mRNA vaccines—namely, BNT162b22Thomas SJ Moreira Jr, ED Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months.N Engl J Med. 2021; (published online Sept 15.)https://doi.org/10.1056/NEJMoa2110345Crossref Scopus (871) Google Scholar (Pfizer-BioNtech) and mRNA-12733Baden LR El Sahly HM Essink B et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (6559) Google Scholar (Moderna)—for roll out in the USA in December, 2020. The efficacies of the BNT162b2 and mRNA-1273 vaccines, with doses administered 21–28 days apart, were 91·1% and 94·1%, respectively, against COVID-19.2Thomas SJ Moreira Jr, ED Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months.N Engl J Med. 2021; (published online Sept 15.)https://doi.org/10.1056/NEJMoa2110345Crossref Scopus (871) Google Scholar, 3Baden LR El Sahly HM Essink B et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (6559) Google Scholar Although these two vaccines showed high efficacy, the trials were done before the emergence of SARS-CoV-2 variants of concern. Variants of concern, especially delta and its derivatives, are the main reason for breakthrough infections globally. Studies have reported breakthrough infections with SARS-CoV-2 variants of concern among BNT162b2-vaccinated and mRNA-1273-vaccinated individuals.4Juthani PV Gupta A Borges KA et al.Hospitalisation among vaccine breakthrough COVID-19 infections.Lancet Infect Dis. 2021; 21: 1485-1486Summary Full Text Full Text PDF PubMed Scopus (118) Google Scholar Therefore, a potential reason for the lower efficacy of CVnCoV compared with BNT162b2 and mRNA-1273 is immune escape by SARS-CoV-2 variants. The available data on breakthrough cases of SARS-CoV-2 suggest the need for booster vaccinations to cope with a waning immune response and emerging SARS-CoV-2 variants. Unlike conventional vaccines, mRNA vaccines are easy to administer, mimic natural infection, cannot become infectious, and are cost-effective to produce at a larger scale. However, higher doses of mRNA vaccines have been shown to increase the rate and severity of adverse events in animal studies.5Pardi N Hogan MJ Pelc RS et al.Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination.Nature. 2017; 543: 248-251Crossref PubMed Scopus (634) Google Scholar Furthermore, data on the comparative safety of different mRNA vaccines are lacking. For low-income countries, the logistics and expenses involved in storing and maintaining mRNA vaccines at low temperatures are challenging. Although mRNA vaccines have been shown to elicit efficacious immune responses in animal models against Zika, rabies, and influenza viruses,6Richner JM Himansu S Dowd KA et al.Modified mRNA vaccines protect against Zika virus infection.Cell. 2017; 168 (25.e10): 1114Summary Full Text Full Text PDF PubMed Scopus (559) Google Scholar, 7Lutz J Lazzaro S Habbeddine M et al.Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines.NPJ Vaccines. 2017; 2: 29Crossref PubMed Scopus (166) Google Scholar to date, only two mRNA-based vaccines have been approved for COVID-19.2Thomas SJ Moreira Jr, ED Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months.N Engl J Med. 2021; (published online Sept 15.)https://doi.org/10.1056/NEJMoa2110345Crossref Scopus (871) Google Scholar, 3Baden LR El Sahly HM Essink B et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (6559) Google Scholar To meet the demand of a global population, sufficient doses will need to be produced within a short amount of time, which will only be feasible with collaboration between vaccine developers and multiple vaccine manufacturers across the globe. Although the efficacy of CVnCoV against COVID-19 partly met the vaccine efficacy criteria of WHO, the time interval for follow-up of 15 days after receiving the second dose was very short. Whether the humoral immune response waned post-vaccination could not be evaluated within such a short period. In February, 2021, Noa and colleagues8Dagan N Barda N Kepten E et al.BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting.N Engl J Med. 2021; 384: 1412-1423Crossref PubMed Scopus (1722) Google Scholar reported a vaccine efficacy of 46% for BNT162b2 in Israel in a real-world scenario. This waning in vaccine efficacy after 6 months in a fully vaccinated population has been attributed to declining humoral immunity and immune escape due to the delta variant. CVnCoV has been withdrawn from regulatory review by its manufacturer and how it would have performed in the real world will now never be known. Vaccine efficacy could be improved via a heterologous boost regimen using vaccines based on two different platforms;9Kant R Dwivedi G Zaman K et al.Immunogenicity and safety of a heterologous prime-boost COVID-19 vaccine schedule: ChAdOx1 vaccine Covishield followed by BBV152 Covaxin.J Travel Med. 2021; (published online Oct 15.)https://doi.org/10.1093/jtm/taab166Crossref PubMed Scopus (15) Google Scholar, 10Liu 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; 398: 856-869Summary Full Text Full Text PDF PubMed Scopus (351) Google Scholar Xinxue Liu and colleagues10Liu 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; 398: 856-869Summary Full Text Full Text PDF PubMed Scopus (351) Google Scholar showed that immunogenicity was higher for heterologous schedules of adenovirus vector-based and mRNA-based vaccines compared with homologous prime-boost schedules. Rather than waiting for higher efficacy vaccines or newer vaccines, existing vaccines could be used in combination with vector-based vaccines in a heterologous boost regimen or as a booster dose to enhance vaccine availability in low-income and middle-income countries to help to end the pandemic. We declare no competing interests. Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trialCVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates. Full-Text PDF