- - Several SARS-CoV-2 variants of concern (VOCs), including i) B.1.1.7; ii) B.1.351; and iii) P.1 variants, have been identified and spreading fast across the world.
- - Evidence indicates that SARS-CoV-2 VOCs might be potentially more dangerous than previous circulating strains due to higher transmissibility, increased disease severity, elevated risk of reinfection, and reduction in vaccine efficacy.
- - Evidence suggests that SARS-COV-2 variants with the E484K mutation in the receptor binding domain (RBD) of the spike protein, such as the B.1.351 and the P.1 VOCs, could pose a serious risk to the effectiveness of current authorized COVID-19 vaccines.
- - Despite the limitations of current evidence (e.g., majority studies are non-peer reviewed), we conclude that there is a possibility that a third wave of pandemic driven by the SARS-CoV-2 VOCs would come. We must take prompt, proper, strict, and uncompromising control measures now.
“Nobody wants a third wave to start, particularly not one comprised of new more communicable variants that can cause real challenges.”
-- Justin Trudeau, Prime Minister of Canada --
To date, COVID-19, caused by the infection of SARS-CoV-2, has resulted in over 110 million cases with more than 2.4 million deaths around the globe (Source). With the vaccines rolling out, we are hoping to end the pandemic along with the extreme uncertainty it brought us as soon as possible. Unfortunately, a new uncertainty and perhaps a greater danger caused by the emergence of COVID-19 variants is looming.
In the past few months, several SARS-CoV-2 variants of concern (VOCs) have been identified in many countries, including i) B.1.1.7, which was first reported in the United Kingdom (UK) in September 2020; ii) B.1.351, which was first identified in October 2020 in cases from South Africa; and iii) P.1, which was detected in Japan in January 2021 from a traveler originating from Brazil.
The SARS-CoV-2 VOCs are spreading fast. For instance, by December 2020, only three months after its first identification, B.1.1.7 had become the dominant SARS-CoV-2 strain in circulation in the UK (Public Health England, 2020). As of February 2021, more than 80 countries have reported cases involving B.1.1.7. The situation was similar for B.1.351 and P.1. About 40 and 17 countries have reported cases associated with B.1.351 and P.1, respectively.
The European Centre for Disease Control and Prevention (CDC), in its most recent risk assessment released on February 15th, 2021, evaluated that “Due to the increased transmissibility, the evidence of increased severity and the potential for the existing licensed COVID-19 vaccines to be partially or significantly less effective against a variant of concern (VOC), combined with the high probability that the proportion of SARS-CoV-2 cases due to B.1.1.7 (and possibly also B.1.351 and P.1) will increase, the risk associated with further spread of the SARS-CoV-2 VOCs in the EU/EEA is currently assessed as high to very high for the overall population and very high for vulnerable individuals” (European CDC, 2021).
There has been a rising fear that current vaccines on the market might have reduced or no efficacy fighting against the SARS-CoV-2 VOCs, and a third wave of COVID-19 pandemic driven by the SARS-CoV-2 VOCs would result. In this OE Original, we examine current available research evidence with regard to B.1.1.7, B.1.351, and P.1 -- three SARS-CoV-2 VOCs, as well as the efficacy of the current authorized vaccines against the VOCs.
- What are the main characteristics of the VOCs (i.e., B.1.1.7, B.1.351, and P.1)?
COVID-19 B.1.1.7 carries a large number of mutations which either change or delete amino acids in viral proteins. One of the key mutations is N501Y, which is a mutation in the receptor binding domain (RBD) of the spike protein at position 501, where the amino acid asparagine (N) has been replaced with tyrosine (Y). Position 501 is a key contact residue in the RBD (Starr et al., 2020). A preprint, running molecular dynamic simulations, demonstrated that N501Y might potentially increase the overall binding affinity between RBD and the human angiotensin-converting enzyme 2 (hACE2) receptor, allowing SARS-CoV-2 a better chance to infect cells (Luan et al., 2021).
Another key mutation in B.1.1.7 is at the position 681 of the spike protein, where proline (P) is replaced by histidine (H). The P681H mutation has been suggested to facilitate respiratory cell entry and transmission (Rambaut et al., 2020). A third key mutation of B1.1.7 is the deletion of amino acids 69 and 70 on the spike protein (S
Both B.1.351 and P.1 have multiple mutations in the RBD of the spike protein, including i) N501Y -- the mutation shared with B.1.17; ii) E484K -- a replacement of glutamic acid with lysine (K) at position 484 of the virus’s spike protein; and iii) K417T -- where the original lysine (K) was replaced by threonine (T). E484K has received particular attention because some studies have found its association with immune escape, including escaping from neutralizing antibodies and increasing the variants’ ability to reinfect (Baum et al., 2020; Greaney, Starr, et al., 2021; Vasques Nonaka et al., 2021; Weisblum et al., 2020).
- How dangerous are the SARS-CoV-2 variants?
First, the SARS-CoV-2 variants seem to be more transmissible than previous predominant stains. Several models projected that B.1.1.7 would result in a substantial increase in transmissibility. For example, in December 2020, the UK New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) estimated an up to 70% increase in transmissibility for B.1.1.7 (Source). On January 15th, 2021, a model established by the United States (US) CDC projected that the B.1.1.7 variant would grow very fast in the US and become the predominant SARS-CoV-2 variant in March 2021 (Galloway et al., 2021). A recent model, created by Davies et al. (2021) and posted on MedRxiv as a preprint on Febuary 7th, 2021, showed that B.1.1.7 was up to 82% [95% credible interval (Crl): 38 to 106%] more transmissible than the pre-existing circulating variants of SARS-CoV-2.
The B.1.351 variant is estimated to be about 50% more transmissible than previous predominant stains (Source). A model estimated that B.1.351 was 1.50 times (95% CrI: 1.20 to 2.13) as transmissible as the previously circulating SARS-CoV-2 variants (Pearson et al., 2021). Currently, little is known about the effects of P.1 on transmissibility. However, the fact that P.1 shares the N501Y mutation with the other two VOCs indicates a possible increased transmissibility for P.1.
The reasons for the increased transmissibility remain unclear. One possible explanation is that the mutations in the spike protein of SARS-CoV-2 may have increased the chance for SARS-CoV-2 to infect cells (Luan et al., 2021). Higher viral loads found in patients infected with SARS-CoV-2 variants may be another possible reason (Kidd et al., 2020). All the hypotheses are a subject for further investigation.
Second, SARS-CoV-2 variants may lead to increased disease severity in patients infected with the variants compared to those infected without the variants. Recently, the UK NERVTAG reported the preliminary results of two unpublished studies done by the London School of Hygiene and Tropical Medicine (LSHTM) and the Imperial College London, respectively (Source). The results of these two studies were consistent. The LSHTM study adopted a Cox proportional hazards model to estimate the change in risk of mortality within 28 days of test for individuals infected with B.1.1.7, and found that the adjusted relative hazard of death was 1.35 [95% confidence interval (CI): 1.08 to 1.68] for individuals infected with B.1.1.7, compared to non-B.1.1.7. The study conducted by the Imperial College London evaluated the differences in mortality between B.1.1.7 cases and non-B.1.1.7 cases, and found that the mean case fatality ratios were 1.36 (95% CI: 1.18 to 1.56) using the case-control weighting method and 1.29 (95% CI 1.07 to 1.54) using the standard method for case fatality ratio, respectively. There is little evidence demonstrating whether B.1.351 or P.1 would cause a change in the severity of COVID-19.
Third, SARS-CoV-2 variants might increase the risk of reinfection, sparking concerns about transmission of SARS-CoV-2 in previously exposed populations. Fortunately, only sporadic cases of reinfection have been documented. A case study reported a case of reinfection with the P.1 variant in a young individual from Brazil with no history of immunosuppression. Nine months after the first infection, the patient again contracted COVID-19 with moderate symptoms, including fever, cough, sore throat, diarrhea, headache, and resting pulse oximetry of 97% (Naveca et al., 2021). A recent preprint on MedRxiv found no evidence that the estimated reinfection rate of B.1.1.7 (0.7%; 95% CI: 0.6 to 0.8) was higher than those of previous strains (Graham et al., 2021). Results from the phase IIb vaccine study conducted by Novavax also showed no significant difference in rates of infection with non-P.1.351 (3.9%) vs. rates of reinfection with P.1.351 (3.9%) (Source).
The fourth but perhaps the most worrisome danger is the probability that SARS-CoV-2 VOCs might reduce the efficacy of current authorized COVID-19 vaccines.
- Are B.1.1.7, B.1.351, and P.1 resistant to current authorized vaccines?
As the COVID-19 vaccines continue to roll out around the world, evidence on the effectiveness of the vaccines in real-world settings is emerging. A preprint released on MedRxiv on February 8th, 2021 estimated that vaccination with the mRNA-based BioNTech/Pfizer vaccine (BNT162b2) reduced the viral load by 1.6-fold to 20-fold in patients who tested positive for SARS-CoV-2 (Petter et al., 2021). Another preprint released on the same day also found that the viral load was reduced four-fold for infections occurring 12-28 days after the first dose of BioNTech/Pfizer vaccine (Levine-Tiefenbrun et al., 2021).
For the B.1.1.7 variant, several studies, mostly preprints, have investigated whether B.1.1.7 is capable of escaping the protection provided by current COVID-19 vaccines, and the results indicated that current authorized vaccines could be expected to be effective against the B.1.1.7 variant. Muik et al. (2021) identified a small but biologically non-significant reduction in the neutralizing titers of SARS-CoV-2 pseudovirus containing the full set of mutations found in the spike protein of B.1.1.7 among patients who received the mRNA-based BioNTech/Pfizer vaccine, compared to the pseudovirus bearing the wildtype spike protein. Another study, using the SARS-CoV-2 pseudovirus containing all mutations found in B.1.1.7 spike protein, also detected a small reduction in neutralizing titers in volunteers who received the BioNTech/Pfizer vaccine (Collier et al., 2021). Small but non-significant reduction in titers of neutralizing antibodies against B.1.1.7 pseudovirus containing a full set of mutations among subjects who received mRNA-based Moderna vaccine (mRNA-1273) was also observed in a study recently published in the New England Journal of Medicine (NEJM); however, all the serum samples obtained from Moderna vaccine recipients neutralized the pseudovirus despite the low titers (Wu et al., 2021).
Results from a preprint released on the Lancet suggested that efficacy of the adenoviral vector-based AstraZeneca vaccine (ChAdOx1 nCoV-19) against B.1.1.7 was similar to that against other non-B.1.1.7 lineages (Emary et al., 2021). The study found that the neutralization activity was 9-fold lower for B.1.1.7, compared to a non-B.1.1.7 lineage. However, vaccine efficacy against symptomatic nucleic acid amplification test positive infection was similar between B.1.1.7 (74.6%; 95%CI: 41.6 to 88.9) and non-B1.1.7 lineages (84%; 95% CI: 70.7 to 91.4) (Emary et al., 2021). The vaccine developed by Novavax (NVX-CoV2373, a protein-based COVID-19 vaccine) showed 87% of vaccine efficacy against B.1.1.7, which was lower than the efficacy against the original SARS-CoV-2 strain (94%) (Source).
More worrying results were seen for B.1.351, which possesses the mutation of E484K. Mutations in the SARS-CoV-2 RBD of the spike protein, which is the main target of serum antibody activity, could impact the activities of serum antibodies (Piccoli et al., 2020). A study conducting comprehensive mapping of mutations found that mutations on E484 in the RBD, including E484K identified in B1.351 and P.1, had the largest effects on neutralization (e.g., 10-fold reduction in neutralization) (Greaney, Loes, et al., 2021). Collier et al. (2021) further demonstrated that introduction of the E484K mutation in a B.1.1.7 background (B.1.1.7 original does not have the E484K mutation) resulted in a more substantial loss of neutralizing activity by BioNTech/Pfizer vaccine-elicited antibodies than the B.1.1.7 mutations alone did.
A preprint found that the BioNTech/Pfizer vaccine recipients’ sera neutralization efficiency was lower (3.4-fold) against the recombinant SARS-CoV-2 strain which contains the E484K mutation (Jangra et al., 2021). They also found that human sera with high neutralization titers were still able to neutralize the recombinant SARS-CoV-2 with E484K mutation, warranting the necessity and importance of inducing highest possible titers in the population by giving two doses of COVID-19 vaccine (Jangra et al., 2021). A new study published in the NEJM showed that neutralization of the B.1.351-spike virus by the human sera from BioNTech/Pfizer vaccine recipients was weaker by approximately 67% than that of the previous SARS-CoV-2 circulating strain, but it still neutralized the B.1.351-spike virus (Liu et al., 2021).
Wang et al. (2021) reported that B.1.351 was significantly resistant to neutralization by the sera (10.3 to 12.4-fold) from the recipients of the Moderna vaccine. An unpublished study found that antibody activity induced by the adenoviral vector-based AstraZeneca vaccine showed very low activity against B1.351, and thereby being not efficacious against mild to moderate COVID-19 caused by B.1.351 (Source). The protein-based vaccine Novavax showed a 49.4% vaccine efficacy against B.1.351 (Source).
Evidence on neutralizing antibodies for the P.1 variant of SARS-CoV-2 is scarce. However, the fact that P.1 variant also has the E484K mutation as the B.1.351 does signify a similarity in the immunity profile.
In this OE Original, we examined current available evidence with regard to three SARS-CoV-2 variants of concern (VOCs) -- B.1.1.7, B.1.351, and P.1, and focused on whether the VOCs would affect the efficacy of current authorized COVID-19 vaccines. First of all, we want to emphasize that current evidence is far from certain and conclusive. We found several limitations. For example, most of the evidence was from preprints in which the peer-review process had not been completed. Additionally, evidence regarding the vaccine efficacy was conducted “in vitro” in the laboratory, which might not reflect the complicatedness of immune response in the population.
Despite the limitations, we may still draw a conclusion that there remains a “realistic possibility” (a term borrowed from the UK NERVTAG, Source) that SARS-COV-2 variants with the E484K mutation in the RBD of the spike protein, such as the B.1.351 and the P.1 VOCs, could pose a serious risk to the effectiveness of current COVID-19 vaccines. A third pandemic wave that is driven by the SARS-CoV-2 VOCs is possible in the near future if we do not take prompt, proper, strict, and uncompromising control measures. As Davies’ et al. (2021) model projected “control measures of a similar stringency to the national lockdown implemented in England in November 2020 are unlikely to reduce the effective reproduction number Rt to less than 1 [for B.1.1.7], unless primary schools, secondary schools, and universities are also closed. We project that large resurgences of the virus are likely to occur following easing of control measures.”
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