key: cord-0888021-zib5721r
authors: Han, Xiucui; Ye, Qing
title: The variants of SARS‐CoV‐2 and the challenges of vaccines
date: 2021-12-15
journal: J Med Virol
DOI: 10.1002/jmv.27513
sha: 5805db77f7e8bc7f8dffd7343b48cecf7ea7c063
doc_id: 888021
cord_uid: zib5721r

Since the outbreak of coronavirus disease 2019 (COVID‐19), countries all over the world have suffered severe losses. It affects not only human life and health but also the economy. In response to COVID‐19, countries have made tremendous efforts to vaccine development. The newly discovered variants of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) have brought major challenges to the effectiveness and research of vaccines. This article reviews the existing literature and summarizes the main variants of the SARS‐CoV‐2 and its impact on vaccines, and provides new ideas for the later development of vaccines. An excellent job in developing and applying vaccines will be an important measure for epidemic prevention and control.

N501Y for gamma, L452R, and T478K for delta, L452Q, and F490S for lambda, and so forth, were observed in RBD. 16 The World Health Organization (WHO) identified variants of concern (VOCs) and variants of interest (VOIs). VOCs have an increment in the virulence and transmissibility or adversely affect the effectiveness of vaccines, diagnostics with clear clinical correlation evidence, and therapeutics. VOIs carry genetic changes, which are predicted or known to reduce the neutralizing effect of antibodies produced against vaccination, affect virulence, transmissibility, immune escape, diagnostics, and the efficacy of treatments. VOIs also can cause significant community transmission. Currently, WHO listed four VOCs, that is, variants B.1.1.7 (alpha), 17-19 B.1.351 (beta), 18,20 P.1 (gamma), 18 and B.1.617.2 (delta) 21 

Adaptive variants in the SARS-CoV-2 genome may change its pathogenic potential and increase drug and vaccine development difficulty ( Figure 1 ). A study found that when the SARS-CoV-2 was incubated with highly neutralized plasma from COVID-19 convalescent patients, the plasma could wholly neutralize the virus for seven passages. However, after 45 days, the deletion of F140 in the N3 loop of the S protein N-terminal domain (NTD) caused a partial breakthrough. On the 73rd day, an E484K substitution occurred in RBD, and then on the 80th day, an NTD N5 loop containing the new glycan sequence was inserted, resulting in an entirely resistant variant to plasma neutralization. The computational model predicts that deletions and insertions in the N3 and N5 loops will prevent the binding of neutralizing antibodies. 27 Viral variants may pose great challenges to current vaccines. If SARS-CoV-2 variants increase their transmissibility or virulence, the importance of public health measures and vaccination will increase.

The global response strategy should also be adjusted in time.

Tracking the variants of viruses requires global efforts. Many research groups isolated SARS-CoV-2 and sequenced it, and the sequencing results were shared in public databases to facilitate the tracking of virus evolution. 28 WHO also uses the shared database to develop and continuously improve the SARS-CoV-2 risk monitoring and evaluation framework to identify and evaluate worrisome variants.

Compared to the SARS-CoV-2 Wuhan reference sequence, all current VOCs have the D614G substitution. Experimental studies have confirmed that the variant containing the D614G substitution has enhanced the binding ability of ACE2 and the replication ability in the human ACE2 knock-in mouse model and in vitro culture (nasal airway epithelium and primary human bronchial culture). 29 The D614G substitution also enhanced the replication and transmissibility of SARS-CoV-2 in hamster and ferret models. 29 The B.1.1.7 (or alpha) variant, reported by the United Kingdom to the WHO, has eight spike mutations which include two deletions, one is in an antibody supersite epitope (Y144), and the other increases infectivity but has little impact on immune escape. 30 The sole RBD mutation is N501Y, which seems to increase the binding ability to the host cell receptor ACE2. Epidemiological analyses quickly ascertained that B.1.1.7 was more transmissible. 31 So far, the B.1.1.7 variant has spread worldwide and has also been noted to acquire the E484K mutation. It is estimated that the sensitivity of this E484K mutant virus to the immune sera of individuals vaccinated with Pfizer/ BioNTech mRNA vaccine is reduced by six times, and the sensitivity to serum during the recovery period is reduced by 11 times. 15 44 P681R is located at the cleavage site of S1-S2, and it seems that strains mutated at this site may have increased replication, resulting in a higher viral load and increased spread. [45] [46] After the patient is infected with this variant, the nucleic acid load of the new coronavirus is particularly high, and the course of the disease progresses faster, and the incubation period is shortened, which is only about 3.2 days. 47 Delta mutant strains can cause hearing impairment, gastrointestinal diseases, and thrombosis. Doctors in India found that patients infected with the delta variant would be more likely to have stomach pain, nausea, vomiting, loss of appetite, hearing impairment, and joint pain. There is little or no evidence that the variants beta and gamma can cause such abnormal clinical symptoms. At the same time, Ganesh Manudhane, a cardiologist from Mumbai, found that some patients infected with delta variant had micro thrombosis or small thrombosis, which could even become gangrene in severe cases.

In addition to the above four variants, we also need to pay attention to other variants types. On June 16, 2021, the WHO an- protein did not escape the T-cell-mediated immunity caused by wild-type S protein. 48 The recent surge in COVID-19 infections is due to the occurrence of RBD comutations that combine two or more infectivity-strengthening mutations.

An experimental study has shown that RBD 2 comutation set The efficacy of the CoronaVac/Sinovac inactivated virus vaccine in Brazil, where 75% of infections were with the P.1 variant, was estimated at around 50% against symptomatic infection. 15 One study has shown that the P.1 variant is not only refractory to multiple neutralizing monoclonal antibodies but also more resistant to neutralization by convalescent plasma (3.4-fold) and vaccine sera (3.8-4.8 folds). 18 The efficacy of the BNT162b2 vaccine was 88.0% (95% CI: 85.3-90.1) with the delta variant after the second dose, while the effectiveness with two doses of the ChAdOx1 nCoV-19 vaccine was lower than with the BNT162b2 vaccine, which was 67.0% (95% CI: 61.3-71.8). 46 

We need more information regarding the protection from an infection that is afforded by the current generation of SARS-CoV-2 vaccines in light of the existing and potential emerging viral VOC.

Although the protection of current vaccines against variants has declined to various degrees, they are still higher or close to the level of protection defined by the WHO of at least 50%. The vaccine is very effective against severe, critical or fatal diseases caused by SARS-CoV-2 infection. In other words, the vaccine retains a certain degree of effectiveness against the variant. Therefore, urgently launching current vaccines to immunize most of the population is currently the best choice to deal with the threat of emerging mutations. Observational studies can also discover whether protection against previously infected variants is lost. When drawing relevant conclusions, relevant confounding factors must be eliminated. If the vaccination rate in the region is too low or the mutation rate is too high to be conducive to statistical stability, observational studies will lack accuracy. The confounding factors of the study can be limited by testing negative studies. [57] [58] [59] In the research on the effectiveness of vaccines, complete sequencing of the isolates at the selected location can reduce the bias in the selection of samples. Samples obtained from unselected vaccine recipients with breakthrough infections and matched unvaccinated controls can be used to assess the impact of specific genomic or antigenic characteristics of interest on vaccine efficacy.

Using these methods in trials or research after vaccine deployment can gather important insights about the correlation of specific virus characteristics, improving the selection of vaccine strains. 60 The trial of new vaccines uses randomized evaluation to get reliable and interpretable results on immunology and clinical endpoints.

When appropriate, placebo controls may be used in communities or subgroups with very limited vaccine supply (e.g., young people) to determine the likelihood of an infected person progressing to severe disease. [61] [62] Randomized trials require additional planning, but where feasible, they can prevent differences in unidentified trial design from confounding research results. 63 

The authors declare that there are no conflict of interests.

Xiucui Han designed the current study and was a major contributor in writing the manuscript. Qing Ye was responsible for the conception, the modification, and giving final approval of the manuscript. The authors read and approved the final manuscript.

Data sharing does not apply to this article as no new data were created or analyzed in this study.

http://orcid.org/0000-0002-1630-4047

Qing Ye http://orcid.org/0000-0002-6756-0630

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