By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: The emergence of SARS-CoV-2 variants may compromise the efficacy of current vaccines.

The Inevitability of Viral Mutations and Emergence of Important Variants

Once SARS-CoV-2 emerged as a disease of humans in November 2019, the emergence of variants of this virus was an inevitability. SARS-CoV-2 has been reported to have an estimated median mutation rate of 1.12 × 10−3 mutations per site-year (95% confidence interval [CI], 9.86 × 10−4 to 1.85 × 10−4).1,2 This actually is less than for some other ribonucleic acid (RNA) viruses, as a consequence of the fact that, unlike many of the others, it has a proofreading mechanism. Thus, it is estimated that SARS-CoV-2 accumulates only two nucleotide changes per month in its genome — a rate of change about half that of influenza and one-quarter that of human immunodeficiency virus. Nonetheless, the unrestrained global replication of SARS-CoV-2 in the face of the selective pressure exerted by the immune system constantly generates enormous numbers of mutation. To possibly make matters worse, it has been suggested recently that, in addition to point mutations and deletions, recombination may occur in this virus.

Viral variants can become dominant only if they have an advantage over other forms of the virus. One important such advantage is increased transmissibility, a characteristic that provides the capability of more rapid spread. This spread potentially may affect not only non-immune populations but possibly also populations with some degree of pre-existing immunity acquired as a result of either prior natural infection or immunization. The consequences of the ability to evade such immunity is the continuation or even worsening of the pandemic.

Some Important Emergent SARS-CoV-2 Variants

A variant strain with a D614G in the viral spike protein associated with increased replication efficiency and transmissibility emerged in March or April 2020 and “took over” from the original Wuhan strain, becoming globally dominant.1-4 The emergence in the United Kingdom in August 2020 of a variant now called B.1.1.7 has further alerted the world to the possibility of its spread and potential consequences. B.1.1.7, which has 17 unique mutations, including three that affect the receptor binding domain of the viral spike protein with N501Y believed to be associated with increased transmissibility, has become a dominant strain in the United Kingdom and has since been detected in the United States (where it is doubling in frequency every 1.5 weeks) and other countries. Its E484K mutation is believed to contribute to resistance to immune clearance of the virus. Laboratory and animal studies suggest increased transmissibility, and epidemiologic studies appear to confirm this. Furthermore, the possibility of an associated increased mortality rate in individuals infected with B.1.1.7 has been raised, although confirmation is necessary.

Another variant, B.1.351 with multiple mutations in the spike protein, emerged in South Africa in October 2020 and has been detected subsequently in other countries, including the United States. Antibody elicited by mRNA-1273m demonstrated significantly (six- to ninefold) reduced potency relative to its effect on B.1.1.7. Furthermore, one study found that antibody from individuals previously infected naturally with SARS-CoV-2 containing the prevalent D614G mutation, but with none of the spike mutations of B.1.351, had significantly reduced neutralizing potency against B.1.351, with IC50s that were six- to 200-fold higher. This suggests that prior infection with the original strain failed to provide full immunity to the new variant. Furthermore, this is consistent with the finding in the Novavax vaccine trial that 30% of placebo recipients had serological evidence of infection prior to enrollment (presumably with the then-prevalent strain of virus), and the rate of subsequent infection did not differ significantly between those with prior infection and those who were seronegative at study entry. B.1.1.7, B.1351, and P1 share some common mutations, such as N501Y and D614G, which are believed to be associated with increased viral transmission.

Two variants of concern have been identified in Brazil — P1, which is dominant in Manaus, and P2, seen throughout the country. P1, which has been detected in the United States, contains three mutations in the spike protein receptor binding domain: K417T, E484K, and N501Y.

Another variant, L452R (CAL-20C), which like the others carries an N501Y mutation, was first seen in Denmark but then emerged in California in the spring and summer of 2020 and began to be detected with increasing frequency in November 2020. Studies performed at the University of California San Francisco detected L452R in 3.8% of samples in mid-December but in 25% by early to mid-January. By early February, this variant accounted for one-third of SARS-CoV-2 isolates sequenced at Stanford. In addition, L452R was associated with a large outbreak at the San Jose Kaiser hospital. The transmissibility and clinical characteristics are yet to be determined, as is the efficacy of vaccines in protection against it.

SARS-CoV-2 Variants and Vaccine Efficacy

The emergence of these variants has raised concern about the efficacy of vaccines.5,6 Fortunately, evidence indicates that antibody elicited in response to either the Pfizer mRNA vaccine, BNT162b2, or the Moderna mRNA vaccine, mRNA-1273m, effectively neutralizes B.1.1.7 (the U.K. variant) in vitro. With the Pfizer vaccine, there is reported to be an approximately 20% decrease in the potency against B.1.351 of the elicited antibody, but experience with influenza virus suggests that this is not a biologically significant loss of activity. The investigational two-dose Novavax vaccine, NVX-CoV2373, is reported to have 89% efficacy in the United Kingdom despite > 50% of infections having been caused by the B.1.1.7 variant. The AstraZeneca vaccine is reported to be effective against symptomatic infection with B.1.1.7 despite the presence of lower neutralizing antibody levels compared to those elicited against the pre-variant strain of the virus. It is reported to effectively prevent severe infection with B.1.351 but to have a lesser effect in preventing mild to moderate infection. As a result of this limited efficacy, South Africa announced on Feb. 7, 2021, that it is suspending its vaccination program with the AstraZeneca vaccine.

Furthermore, although a single dose of the Johnson & Johnson Ad26 vaccine (which will be reviewed by the U.S. Food and Drug Administration [FDA] on Feb. 26) demonstrated protective efficacies against symptomatic COVID-19 at 28 days of 72% (85% against severe disease and 100% against hospitalization or death) in a trial in the United States, it was less effective at 66% in Latin America and 57% in South Africa. This provided strong evidence of its reduced efficacy in countries with prevalent viral variants. One or more of the mutations in P1 likely account for the limited efficacy of the investigational Sinovac vaccine in Brazil, which may be as low as 50%. Vaccine efficacy against the L452R California variant has not been reported.

Additional variants of concern will continue to emerge and, in some cases, dominate. As a consequence, careful genotypic surveillance is critical. The adverse effects of some variants on the efficacy of naturally acquired or vaccine-acquired immunity is of obvious concern, and plans to address this are ongoing. Moderna has indicated that it plans Phase I trials evaluating two different strategies designed to deal with B.1.351. In one, a booster dose of the existing vaccine will be administered, while in the other, boosting will be achieved with an altered vaccine that incorporates the variant’s mutations.

An important question is: How long would it take to have a new vaccine available to counter variants? Jennifer Haller received the first dose of the Moderna vaccine 66 days after scientists in the United States were able to view the published genetic code of SARS-CoV-2. If modification of a vaccine is required to deal with variants, the vaccine itself presumably could be developed in a matter of weeks. Subsequent testing would be truncated, involving smaller numbers of patients than did the parent vaccine, and the initial use of a surrogate, such as the development of neutralizing antibody, could be considered as sufficient for initial authorization. Subsequent studies could examine other more traditional endpoints.

SARS-COV-2 Variants: Other Considerations

The emergence of variants causes additional complicating issues. Thus, the FDA has warned of the potential for leading to falsely negative diagnostic polymerase chain reaction (PCR) results with some manufacturers’ tests, and concern also has been raised about the potential lack of efficacy of some therapeutic monoclonal antibodies.

It is clear that SARS-CoV-2 will never disappear and that humanity will have to control it and live with it with the critical aid of effective vaccines. It also seems likely that this will involve an ongoing struggle with continual surveillance for the emergence of “escape mutants” and the potential need to modify vaccines accordingly.

REFERENCES

  1. Centers for Disease Control and Prevention. SARS-CoV-2 variants. Updated Jan. 31, 2021. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
  2. Koyama T, Platt D, Parida L. Variant analysis of SARS-CoV-2 genomes. Bull World Health Organ 2020;98:495-504.
  3. Galloway SE, Paul P, MacCannell DR, et al. Emergence of SARS-CoV-2 B.1.1.7 lineage - United States, December 29, 2020-January 12, 2021. MMWR Morb Mortal Wkly Rep 2021;70:95-99.
  4. Zimmer K. A guide to emerging SARS-CoV-2 variants. The Scientist. Jan. 26, 2021. https://www.the-scientist.com/news-opinion/a-guide-to-emerging-sars-cov-2-variants-68387
  5. Xie X, Liu Y, Liu J, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K, and N501Y variants by BNT162b2 vaccine-elicited sera. bioRxiv 2021; Jan 27:2021.01.27.427998. doi: 10.1101/2021.01.27.427998. [Preprint].
  6. Moore JP, Offit PA. SARS-CoV-2 vaccines and the growing threat of viral variants. JAMA 2021; Jan 28. doi: 10.1001/jama.2021.1114. [Online ahead of print].