New variants of SARS-CoV-2 – clinical, public health and vaccine implications

For the publisher:

Worldwide, there are multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Variants of SARS-CoV-2 have been classified by the Centers for Disease Control and Prevention (CDC) as variants of interest, variants of concern and variants of great consequence. Three new variants¹ which quickly became dominant in their countries have raised concerns: B.1.1.7 (also known as VOC-202012/01), 501Y.V2 (B.1.351) and P.1 (B.1.1.28.1).

Variant B.1.1.7 (23 mutations with 17 amino acid changes) was first described in the United Kingdom on December 14, 2020; the 501Y.V2 variant (23 mutations with 17 amino acid changes) was first reported in South Africa on December 18, 2020; and variant P.1 (approximately 35 mutations with 17 amino acid changes) was reported in Brazil on January 12, 2021. On February 22, 2021, variant B.1.1.7 was reported in 93 countries, 501Y. V2 variant in 45 and the P.1 variant in 21.¹ All three variants have the N501Y mutation, which changes the amino acid asparagine (N) to tyrosine (Y) at position 501 in the spike receptor-binding domain. The 501Y.V2 and P.1 variants have two additional mutations in the receptor binding domain, K417N / T and E484K. These mutations increase the binding affinity of the receptor binding domain to the angiotensin-converting enzyme 2 (ACE2) receptor. Four main concerns arising from the emergence of the new variants are their effects on viral transmissibility, severity of the disease, rates of reinfection (ie escape from natural immunity) and vaccine effectiveness (ie escape from vaccine-induced immunity).

The 501Y.V2 variant spread rapidly in South Africa, accounting for 11% of the sequenced viruses (44 of 392) in the first week of October 2020, to 60% of the sequenced (302 of 505) in the first week of November of 2020, and for 87% of those sequenced (363 of 415) in the first week of December 2020. In Western Cape, a South African province where the 501Y.V2 variant is prevalent, a limit of 100,000 cases of Covid-19 has been reached approximately 50% more quickly in the second wave of infection than in the first wave (54 vs. 107 days). The 501Y.V2 variant was estimated at 50%^two more transmissible than pre-existing variants in South Africa, and B.1.1.7 between 43% and 82%³ more transmissible than the pre-existing variants in the United Kingdom.

The rates of hospitalization of diagnosed cases and the clinical profile of inpatients were similar in the first and second waves in the Western Cape. However, a preliminary analysis by the National Institute for Communicable Diseases showed that the 501Y.V2 variant was associated with hospital mortality 20% higher in the second wave in South Africa than in the first. This finding was mainly due to the greater transmissibility of this variant, which quickly overburdened health services and compromised the timely access to hospital care and the quality of that care. Evidence from the United Kingdom indicates that variant B.1.1.7 may be associated with a higher risk of death than pre-existing variants in the United Kingdom.⁴ Although there is no evidence that antiviral agents and anti-inflammatory treatments are less effective with emerging variants than with pre-existing variants, treatment with convalescent serum and monoclonal antibodies may not be as effective.

Regarding the escape of natural immunity, variant B.1.1.7 showed a modest decrease in neutralization activity, by a factor of 1.5, while variant 501Y.V2 showed complete escape of neutralizing antibodies in 48% of the samples of convalescent serum (21 of 44) obtained from patients who had previously had Covid-19.⁵ A random finding from a vaccine trial in South Africa, in which 31% of enrolled participants had previously been infected with SARS-CoV-2, was that the incidence of Covid-19, confirmed in the polymerase chain reaction, was 7.9% among seronegative subjects and 4.4% among seropositive subjects in the placebo group. This finding indicates that previous infection with pre-existing variants may provide only partial protection against reinfection with the 501Y.V2 variant.

Table 1. Table 1. Summary results on the effectiveness of the SARS-CoV-2 vaccine trial and viral neutralization of variants B.1.1.7, P.1 and 501Y.V2, compared to pre-existing variants.

Regarding the escape of immunity induced by the vaccine, variant B.1.1.7 showed modest decreases in neutralizing activity in serum samples obtained from vaccinated persons (table 1) The serum neutralization activity for the 501Y.V2 variant among vaccinated persons was lower by a factor of 1.6 to 8.6 for the BBIBP-CorV vaccine, the BNT162b2 vaccine and the mRNA-1273 vaccine, but it was lower by a factor of up to 86, including complete immune escape, for the AZD1222 vaccine (table 1) The neutralizing activity for variant P.1 among vaccinated persons was lower by a factor of 6.7 for the BNT162b2 vaccine and by a factor of 4.5 for the mRNA-1273 vaccine (table 1) The clinical relevance of lower neutralizing activity for mild or severe Covid-19 is unclear, but the efficacy in clinical trials was less for all three vaccines tested in the middle of transmission of the 501Y.V2 variant in South Africa than efficacy in trials conducted in countries with pre-existing variants. Efficacy was greater by a factor of 3.2 with the AZD1222 vaccine in the United Kingdom and Brazil than in South Africa (70% vs. 22%), greater by a factor of 1.8 with the NVX-CoV237 vaccine in United Kingdom than in South Africa (89% vs. 49%), and higher by a factor of 1.3 with the Ad26.COV2.S vaccine in the United States than in South Africa (72% vs. 57% ).

The emergence of these three new worrying variants highlights the importance of surveillance with genomic surveillance for the early identification of future variants. Recently, two more variants of SARS-CoV-2, B.1.427 and B.1.429, which were first detected in California, have been shown to be approximately 20% more transmissible than the pre-existing variants and have been classified by the CDC as worrying variants. The potential of variants to escape naturally induced and vaccine-induced immunity makes the development of next generation vaccines that induce broad neutralizing activity against current and future potential variants a priority. The suppression of viral replication with public health measures and the equitable distribution of vaccines is critical to reduce the risk of generating new variants.

Salim S. Abdool Karim, MB, Ch.B., Ph.D.
Center for AIDS Research Program in South Africa, Durban, South Africa
[email protected]

Tulio de Oliveira, Ph.D.
KwaZulu-Natal Research and Sequencing Research Platform (KRISP), Durban, South Africa

This letter was published on March 24, 2021, at NEJM.org.