Is the SARS-CoV-2 delta variant threatening vaccine efficacy?
A new study in the UK, by researchers at Imperial College London, The Francis Crick Institute and the University of Glasgow, explores the loss of coronavirus disease 2019 (COVID-19) vaccine efficacy against the virus behind the current pandemic caused by the emergence of newer variants that have undergone mutational escape. The paper, available on the medRxiv* preprint server, shows that the delta and beta variants, in particular, are associated with lower neutralizing efficacy compared to the alpha variant or the original Wuhan strain. Background  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in a cluster of cases in China at the end of 2019, which then spread rapidly and widely to involve the whole world in the ongoing pandemic of coronavirus disease 2019 (COVID-19). In the absence of any effective and safe antiviral pharmaceutical measure, non-pharmaceutical interventions have been resorted to. Simultaneously, several vaccines were developed at record speed (over the period of one year) and gained emergency use authorization (EUA) for deployment against the virus. The first vaccines to be approved were the messenger ribonucleic acid (mRNA) vaccines from Moderna and Pfizer, both with approximately 95% efficacy against symptomatic COVID-19. Others followed, notably the adenovirus-vector vaccine from AstraZeneca. However, the emergence of new variants of concern (VOCs) of the virus poses a threat to the efficacy of the vaccines currently available, especially in the context of the delayed-second-dose strategy used in the UK at present to maximize vaccine coverage, with the second dose within 12 weeks rather than 4. Among the most concerning is the delta variant B.1.617.2, first reported from India, but which rapidly rose to dominance in the UK, displacing the alpha VOC B.1.1.7. The delta variant contains genomic mutations that alter the receptor-binding domain (RBD), including L452R and E484Q, that have been shown to confer immune evasion capabilities in other SARS-CoV-2 lineages. The former is found in the lineage B.1.427/B.1.429, a variant of interest (VOI) first identified in California that has been observed to resist neutralization by convalescent or vaccine recipient sera. The latter seems to have a similar impact as that of E484K, which reduces antibody binding. Existing data  Public Health England (PHE) and Public Health Scotland (PHS) data indicate higher neutralization titers after two doses of either vaccine, along with weaker neutralization of the delta variant. In fact, a single dose of vaccine neutralized half the alpha variant, but only 33% of viral particles of the alpha variant. With two doses, the efficacy was 93% with the alpha variant compared to 88% with the delta variant. Cases detected after one or two doses of the vaccine were more likely to be caused by the delta VOC rather than the alpha lineage (40% higher odds). The alpha lineage is marked by the failure of the Spike gene detection on reverse transcriptase-polymerase chain reaction (RT PCR). Using this criterion, the scientists in the EAVE-2 study showed that the Pfizer vaccine efficacy was 92% against all spike-non-detector strains (taken to be alpha variant), vs. 79% for those who were spike-positive (taken to be the delta variant). With the AstraZeneca vaccine, the efficacy went down from 73% in the spike-negative group compared to 60% in the spike-positive cohort. Lower neutralization efficacy  The current study compared the BNT162b2 and ChAdOx1 vaccines (from Pfizer and AstraZeneca, respectively) for their neutralization of the original Wuhan lineage against the delta and the beta variants. The latter VOCs have been shown to be more resistant to neutralization and breakthrough infection in clinical trials. Using the HIV (SARS-CoV-2) pseudovirus system, the neutralizing efficacy was 4 to 6-fold lower against the B.1.617.1, B.1.617.2 and B.1.351 variants compared to the Wuhan variant. Two doses were associated with higher neutralizing efficacy against both the Wuhan and beta variants, and to a lesser extent, against the delta variant too. Comparing the two vaccines, the AstraZeneca vaccine produced between 0.7 to 4-fold lower neutralizing activity against the B.1.351, B.1.617.1 and B.1.617.2 compared to the Wuhan strain. The Pfizer variant produced higher neutralizing titers after two doses compared to one dose, as well as compared to two doses of the AstraZeneca vaccine. The latter also produced a lower mean antibody titer compared to the Pfizer vaccine. However, the Pfizer vaccine still showed 8 to 11-fold lower neutralizing titers against B.1.351, B.1.617.1 and B.1.617.2 VOCs, respectively. Comparison with other studies  These findings accord with other recent studies that show vaccine antisera being about 6-fold less potent in the neutralization of the delta compared to the earlier strains of the virus, but preserving efficacy with the beta lineage. Like the current study, these earlier papers were based on antisera from vaccine recipients in the real world and not in clinical trials. Clinical trial data continues to show preserved efficacy against the delta strains, as well as the B.1.618 and B.1.525 lineages, in live virus neutralization studies. The geometric mean plaque reduction neutralization titers were lower for the B.1.617.1 variant relative to the wildtype USA-WA1/2020 virus. Despite this, all the antisera successfully neutralized all variants at uniform titers, all at 40 or above. These differences may be due to the variation in methods or antisera used in different studies, say the scientists. In December 2020, the Pfizer vaccine was rolled out, prioritizing the healthcare workers and elderly, while the AstraZeneca vaccine was added in January 2021 and the Moderna vaccine from April 2021. An important caveat in making these comparisons is the difference in the age group between the vaccine recipients. The AstraZeneca vaccine recipients were 15 years older, on average, than Pfizer vaccine recipients, because of the changing vaccine procurement over time in the UK, along with the successive targeting of younger and younger age groups with each round of vaccination. This will require further research using larger samples with age-matched vaccine recipients. The UK drive to cover as much of the population with one dose of the vaccine, at least, with the second dose within 12 weeks, was successful in reducing severe and critical cases, and deaths, due to COVID-19. However, the delta variant threatens this success, along with the beta variant. Nonetheless, the new wave of infections is not accompanied by a surge in hospitalizations among vaccine recipients, indicating that the vaccines are able to dampen disease severity even with low antibody responses. A growing threat is that with a single dose of the vaccine, or with those who had prior infection with another variant, infection with the delta variant may still be transmitted at high rates, promoting the emergence of variants that are resistant to neutralization by vaccine-induced antibodies. Even among those who have been fully vaccinated, the waning of antibody titers over time may promote reinfections later on. The investigators comment:  Trials investigating whether a third dose of vaccine based on the original Wuhan-Hu-1 virus or adapted virus variants will help to prevent symptomatic infection with B.1.617.2 and future virus variants are underway.  *Important notice  medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.