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      Friday, June 24, 2022
      For You News & Perspective Drugs & Diseases CME & Education Academy Video Decision Point
      Drugs & Diseases > Infectious Diseases > COVID-19 Vaccines Q&A

      What are viral variants in COVID-19 and how are they affecting vaccine immune responses?

      Updated: Sep 24, 2021
      • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: John L Brusch, MD, FACP  more...
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      Answer

      Mutations

      Viral mutations may naturally occur anywhere in the SARS-CoV-2 genome. Unlike the human DNA genome, which is slow to mutate, RNA viruses are able to readily, and quickly, mutate. A mutation may alter the viral function (eg, enhance receptor binding), or may have no discernable function. A new virus variant emerges when the virus develops 1 or more mutations that differentiate it from the predominant virus variants circulating in a population. The CDC surveillance of SARS-CoV-2 variants includes US COVID-19 cases caused by variants. The site also includes which mutations are associated with particular variants. The CDC has launched a genomic surveillance dashboard and a website tracking US COVID-19 case trends caused by variants. Researchers are studying how variants may or may not alter the extent of protection by available vaccines.

      Variants of concern

      Variants of concern (VOCs) may reduce vaccine effectiveness, which may be evident by a high number of vaccine breakthrough cases or a very low vaccine-induced protection against severe disease. The CDC tracks variant proportions in United States and estimates the B.1.617.2 (Delta) variant accounts for approximately 82% of cases as of July 17, 2021. The rapid spread over 6 weeks to become the dominant strain is thought to be due to increased transmissibility of this variant, compared with wild-type or previous variants (eg, B.1.1.7). 

      On June 15, 2021, the CDC named the Delta variant (B.1.617.2) that originated in India a variant of concern in the United States. As of mid-June 2021, the CDC estimates the Delta variant accounts for 10% of new cases in the United States.  

      Enhanced genomic surveillance in some countries have detected other VOCs. These include B.1.351 (501Y.V2) first detected in South Africa and the B.1.1.28 (renamed P.1) (501Y.V3), which was detected in 4 travelers from Brazil during routine screening at the Tokyo airport. [42]  A change of the B.1.1.7 variant that includes the E484K mutation (B.1.1.7+E484K) was discovered in early 2021 that furthers these concerns. The CDC is also tracking VOCs B.1.427 and B.1.429, which emerged in California. 

      The immune response provoked by vaccines includes protection from the antigen by eliciting antibodies, T-cells, and interferons. Variants that have emerged in the United Kingdom and South Africa in late 2020 have multiple mutations in their S glycoproteins (ie, the spike protein), which are key targets of currently available vaccines. [43]  

      BNT162b2 vaccine 

      A two-thirds reduced neutralization of BNT162b2 vaccines against the B.1.351 variant was shown in vitro when compared with the reference viral strain. [44]  

      Other in vitro studies comparing sera of neutralizing antibody titers from participants in vaccine studies described use of sera from BNT162b2 SARS-CoV-2 vaccine showed no reduction in neutralization of pseudoviruses bearing the B.1.1.7 variant (ie, UK variant) [43, 45] and the B.1.351 variant (ie, South African variant). [43]  

      However, another study suggests that antibodies elicited by primary infection and by the BNT162b2 mRNA vaccine are likely to maintain protective efficacy against B.1.1.7 and most other variants, but that the partial resistance of virus with the B.1.351 spike protein could render some individuals less well protected, supporting a rationale for the development of modified vaccines containing the E484K mutation.31 

      The Delta variant (B.1.617.2) has rapidly spread in India is emerging in the United States mid-2021. It became the predominant variant in the United Kingdom during Spring 2021. Edra et al found this variant 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and mRNA vaccinated individuals. [47] However, a study completed by Public Health England found the BNT162b2 vaccine was slightly reduced from 93.4% with the B.1.1.7 variant to 87.9% for the Delta variant 2 weeks after the second dose. [48]  Another U.K. analysis found single-dose recipients neutralizing antibodies are significantly lower against B.1.617.2 and B.1.351 VOCs relative to B.1.1.7, implying that although a single dose might still afford considerably more protection than no vaccination, single-dose recipients are likely to be less protected against these SARS-CoV-2 variants. [49] These data stress the importance of receiving 2 doses and adhering to the typical regimen of injections approximately 3 weeks apart. 

      mRNA-1273 vaccine

      Similarly, the mRNA-1273 vaccine neutralizing capabilities were assessed against the UK and South African variants. No significant impact on neutralization against the B.1.1.7 variant was detected in the first phase of testing and reported in February 2021. In contrast, just a month later, decreased titers of neutralizing antibodies were observed against the P.1 variant, the B.1.427/B.1.429 variant (versions 1 and 2), the B.1.1.7+E484K variant, and the B.1.351 variant as well as a subset of its mutations in the RBD. The researchers detected reductions by a factor of between 2.3 and 6.4 in titers of neutralizing antibodies against the tested panel of variants. The largest effect on neutralization, reduction by a factor of 6.4, was measured against the B.1.351 variant. [50]   

      Edra et al estimated the Delta variant (B.1.617.2), first identified in India, to be 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and mRNA vaccinated individuals. [47]  

      A slight decreased neutralization is not considered to be clinically significant regarding vaccine efficacy, owing to the very high efficacy of each mRNA vaccine (ie, approximately 95%) to the Wuhan reference viral strain. Continued variant surveillance in both nonhuman primates and humans will allow foresight for any needed changes to vaccine development or future booster doses that may be warranted. In February, 2020, Moderna announced it is advancing its variant-specific vaccine candidate, mRNA-1273.351, against the B.1.351 variant first identified in South Africa into preclinical studies and a Phase 1 study in the United States. A multivalent booster candidate, mRNA-1273.211, which combines mRNA-1273 and mRNA-1273.351 in a single vaccine and a third lower-dose of mRNA-1273 vaccine have also been forwarded to the National Institutes of Health for phase 1 clinical testing. 

      NVX-CoV2373 vaccine

      Novavax confirmed preliminary efficacy results for NVX-CoV2373 vaccine from the phase 3 trial in the UK (n > 15,000). The final analysis showed vaccine efficacy of 96.4% against the original strain of SARS-CoV-2. [40]    

      Final analysis from the Phase 2b trial (n > 4,400) conducted in South Africa for NVX-CoV2373 reported 55.4% efficacy among HIV-negative participants. The South African escape variant was the predominant variant (more than 90% of cases analyzed). [40]  

       Ad26.CoV2.S vaccine 

      Johnson & Johnson reported phase 3 trial results (EMSEMBLE; n= 43,783) for their single-dose Ad26.COV2.S viral vector vaccine in late January 2021. The trial was conducted in geographical regions and during the time when several variants emerged. FDA analysis at Day 28 determined the vaccine was 72% effective in the US, 61% in Latin America, and 64% in South Africa at preventing moderate-to-severe COVID-19 infection. Importantly, the vaccine was 85% effective in preventing severe disease and provided complete protection against COVID-related hospitalization and death in all geographic regions. Additionally, it showed consistent protection across all variants and regions studied, including South Africa where nearly all cases of COVID-19 (95%) were due to infection with a SARS-CoV-2 variant from the B.1.351 lineage. [34]  

      AZD-1222 (ChAdOx1 nCoV-19) vaccine

      A study in the UK between October 1, 2020 and January 14, 2021 determine efficacy of AZD-1222 against the B.1.1.7 variant is similar to the efficacy of the vaccine against other lineages. [51]   

      Minimal protection against mild-to-moderate COVID-19 infection from the B.1.351 variant in South Africa was observed following 2 doses in non-HIV infected young adults (n ~2000). Mild-to-moderate COVID-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9%. Among the 42 participants with COVID-19, 39 cases (92.9%) were caused by the B.1.351 variant. The incidence of serious adverse events was balanced between the vaccine and placebo groups. These results prompted South Africa to halt roll out of the vaccine in early February. [52]   

      A study completed by Public Health England found 2 dose effectiveness reduced from 66.1% for the B.1.1.7 variant to 59.8% for the B.1.617.2 variant (Delta) first identified in India, which is the dominant variant in the United Kingdom as Spring 2021. [48]  

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