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SARS-CoV-2 mutations, vaccines, and immunity: implication of variants of concern

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Ji Yun Noh
Ji Yun Noh
Ji Yun Noh
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Hye Won Jeong at Chungbuk National University
Hye Won Jeong
Eui-Cheol Shin
Eui-Cheol Shin
Eui-Cheol Shin
  • This person is not on ResearchGate, or hasn't claimed this research yet.
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RESEARCH HIGHLIGHT OPEN
SARS-CoV-2 mutations, vaccines, and immunity: implication
of variants of concern
Ji Yun Noh
1,2
, Hye Won Jeong
2,3
and Eui-Cheol Shin
2,4
Signal Transduction and Targeted Therapy (2021) 6:203 ; https://doi.org/10.1038/s41392-021-00623-2
In a recent study published in Nature, Wang et al.
1
investigated the
neutralizing activities of antibodies elicited by COVID-19 mRNA
vaccines and natural infection with SARS-CoV-2 against SARS-CoV-
2 variants.
The devastating impact of the ongoing COVID-19 pandemic on
public health, the economy, and society has made vaccine
development a top priority for global health. Thus, vaccine
development is progressing at an unprecedented pace as an
urgent response to COVID-19.
Currently, there are four main types of COVID-19 vaccine:
nucleic acid (mRNA and DNA), viral vector, protein subunit, and
inactivated virus. Two COVID-19 mRNA vaccines (BNT162b2
developed by Pfizer-BioNTech and mRNA-1273 by Moderna) have
been authorized by the U.S. Food and Drug Administration (FDA)
and European Medicines Agency (EMA). In addition, Ad26.COV2.S
(Johnson & Johnson/Janssen) was approved by the FDA and EMA
and ChAdOx1 nCoV-19 (AstraZeneca) was authorized by the EMA,
both of which are viral vector vaccines.
BNT162b2 and mRNA-1273 are lipid nanoparticle-formulated,
nucleoside-modified RNA vaccines encoding the prefusion spike
glycoprotein of SARS-CoV-2. Both of them have shown favorable
vaccine efficacy (94–95%) in preventing COVID-19 in phase 3
clinical trials. However, emerging variants of SARS-CoV-2 and its
global expansion have raised concerns about potentially reduced
protection against variants of concern (VOCs) by current COVID-19
vaccines. Notable variants harboring multiple mutations in the
spike protein have emerged in the United Kingdom (B.1.1.7),
South Africa (B.1.351), and Brazil (P.1). B.1.1.7 variant (20I/501Y.V1),
the most globally widespread VOC, has a N501Y substitution in
the receptor-binding domain (RBD), H69/V70 deletion in the N-
terminal domain, and P681H mutation adjacent to the furin
cleavage site in the spike protein. This variant has been associated
with increased transmissibility. B.1.351 variant (20H/501Y.V2)
contains several mutations, including K417N, E484K, and N501Y.
P.1 variant (B.1.1.28.1) possesses K417T, E484K, and N501Y
substitution in the RBD of the spike protein. These VOCs also
share the D614G mutation, which confers an increased ability for
rapid viral spread.
Wang et al.
1
tested the neutralizing activity of plasma from
vaccinees (BNT162b2, n=6; mRNA-1273, n=14) against pseudo-
type viruses harboring K417N, E484K, N501Y, and a combination
of these three RBD mutations (B.1.351 variant). The study revealed
1- to 3-fold decreased neutralizing activity against E484K, N501Y,
and the K417N:E484K:N501Y combination (p=0.0033, p=0.0002,
and p< 0.0001, respectively), but there was no significant
difference in neutralizing activity against wild-type and K417N
mutation. This result suggests that COVID-19 mRNA vaccine-
elicited neutralizing antibodies are less effective against emerging
SARS-CoV-2 VOCs with RBD mutations. In addition, convalescent
plasma obtained 6 months after SARS-CoV-2 infection was 0.5- to
20.2-fold less effective in neutralizing the K417N:E484K:N501Y
combination (p< 0.0001).
In a subsequent analysis, the study was extended to SARS-CoV-2
RBD-specific memory B cells. The mRNA vaccines elicited a robust
SARS-CoV-2 RBD-specific memory B-cell response similar to
natural infection. Monoclonal antibodies (mAbs) were expressed
by SARS-CoV-2 RBD-specific memory B cells and had potent
neutralizing activity towards SARS-CoV-2 pseudovirus. However,
among the 17 most potent mAbs, 14 demonstrated reduced or
abolished activities in neutralizing the K417N, E484K, or N501Y
mutations. Selection pressure by mAbs was also detected; these
mutations emerged when recombinant vesicular stomatitis virus/
SARS-CoV-2 S was cultured in the presence of the vaccine-
elicited mAbs.
Similarly, Chen et al.
2
reported that sera from BNT162b2-
vaccinated individuals showed reduced neutralizing activities
against emerging SARS-CoV-2 variants. They observed significantly
decreased neutralizing potency of sera from the vaccinees against
B.1.1.7 isolate (2-fold), E484K/N501Y/D614G recombinant variant
(4-fold), and two chimeric SARS-CoV-2 strains encoding
B.1.351 spike (10-fold) and P.1 spike (2.2-fold) compared to the
D614G variant in Vero-hACE2-TMPRSS2 cells. A notable reduction
in neutralizing activity was not shown with the K417N/D614G
variant, suggesting that sera from recipients of the BNT162b2
vaccine had a lower neutralizing capacity against E484K and
N501Y-containing viruses.
In addition, Wang et al.
3
demonstrated a substantial loss of
neutralizing activity against the B.1.351 strain in convalescent
plasma (9.4-fold) and sera from vaccinees who received mRNA
vaccines (10.3–12.4-fold). E484K seemed to be the main
contributor to the neutralization resistance. Furthermore, the
neutralizing potency of mAb therapeutics in clinical use or
under clinical investigation decreased against the B.1.351
variant.
Received: 17 March 2021 Revised: 2 April 2021 Accepted: 24 April 2021
1
Division of Infectious Diseases, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea;
2
Graduate
School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea;
3
Division of Infectious Diseases,
Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea and
4
The Center for Epidemic Preparedness, KAIST, Daejeon,
Republic of Korea
Correspondence: Eui-Cheol Shin (ecshin@kaist.ac.kr)
These authors contributed equally: Ji Yun Noh, Hye Won Jeong.
www.nature.com/sigtrans
Signal Transduction and Targeted Therapy
©The Author(s) 2021
1234567890();,:
Taken together, the results from recent studies suggest that
the emergence of resistant SARS-CoV-2 variants may nullify the
effects of current COVID-19 vaccines. However, COVID-19
vaccines can elicit not only neutralizing antibodies, but also
SARS-CoV-2-specificCD4
+
and CD8
+
T-cell responses. Vaccina-
tion with various vaccine platforms, including mRNA and viral
vectors, has been shown to elicit SARS-CoV-2-specificCD4
+
and
CD8
+
T-cell responses (Fig. 1). In principle, it is more difficult to
evade T-cell responses than a neutralizing antibody response
because multiple T-cell epitopes are scattered across viral
proteins, whereas neutralizing antibody targets a narrow region
in the viral protein. Although SARS-CoV-2 mutations that
abrogate binding to major histocompatibility complex have
been reported,
4
Tarke et al.
5
recently reported an insignificant
impact of SARS-CoV-2 variants on both CD4
+
and CD8
+
T-cell
responses in COVID-19 convalescents and recipients of COVID-
19 mRNA vaccines. T-cell responses to the variants B.1.1.7,
B.1.351, P.1, and CAL.20C (emerged in Southern California) were
not differ from those to the ancestral strain of SARS-CoV-2. Most
SARS-CoV-2 T-cell epitopes were conserved despite the muta-
tions in the variants.
The future of the current COVID-19 pandemic is unpredict-
able. Careful surveillance for the emergence of variants and a
thorough investigation of its impact on public health will be
continuously required. Continuous emergence of SARS-CoV-2
VOCs have implications for updating current COVID-19 vaccines
and the development of vaccines providing broader protection.
Even if SARS-CoV-2 variants escape the neutralizing antibodies
elicited by current COVID-19 vaccines, T-cell immunity may be
helpful in reducing the disease burden of COVID-19 by
attenuating disease severity and decreasing mortality. The
real-world effectiveness of the COVID-19 vaccines, especially in
preventing hospitalization, complications, and death, should be
assessed in the near future. Above all, public health policies
should be implemented to ensure that concerns about SARS-
CoV-2 variants and possible reduced vaccine efficacy towards
VOCs do not lead to blunted COVID-19 vaccination rates.
ACKNOWLEDGEMENTS
This research was supported by the 2020 Joint Research Project of Institutes of
Science and Technology, the Korea Health Technology R&D Project through the
Korea Health Industry Development Institute (KHIDI), funded by the Ministry of
Health & Welfare, Republic of Korea (grant number: HI20C0452), and the National
Research Foundation of Korea (NRF) grant funded by the Korea government (MISP)
(2020R1A5A2017476).
ADDITIONAL INFORMATION
Competing interests: The authors declare no competing interests.
REFERENCES
1. Wang, Z. et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating
variants. Nature 592, 616–622 (2021).
2. Chen, R. E. et al. Resistance of SARS-CoV-2 variants to neutralization by monoclonal
and serum-derived polyclonal antibodies. Nat. Med. 27, 717–726 (2021).
3. Wang, P. et al. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7.
Nature 593, 130–135 (2021).
4. Agerer, B. et al. SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8(+)
T cell responses. Sci. Immunol. 6, eabg6461 (2021).
5. Tarke, A. et al. Negligible impact of SARS-CoV-2 variants on CD4
+
and CD8
+
T cell
reactivity in COVID-19 exposed donors and vaccinees. Preprint at bioRxiv https://
doi.org/10.1101/2021.02.27.433180 (2021).
Open Access This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly
from the copyright holder. To view a copy of this license, visit http://creativecommons.
org/licenses/by/4.0/.
© The Author(s) 2021
Fig. 1 COVID-19 vaccines elicit SARS-CoV-2-specific CD4
+
and CD8
+
T-cell responses as well as neutralizing antibodies. Even though
antibodies elicited by current COVID-19 mRNA vaccines had shown diminished neutralizing activities against SARS-CoV-2 variants, T-cell
responses may have a role for host protection against SARS-CoV-2 variants
SARS-CoV-2 mutations, vaccines, and immunity: implication of variants of. . .
Noh et al.
2
Signal Transduction and Targeted Therapy (2021) 6:203
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... Scientific research of RNA coronaviruses impacting the current pandemic has been developing for over two decades and of extreme necessity became further intensified with the onset of COVID-19 by early 2020. [8][9][10] These research studies culminated in numerous clinical trials of multiple newly developed COVID-19 vaccines in 2020, some using the recently developed mRNA and other molecular models, and with recommendations for booster shots that encompassed recently evolved epitopes discovered in some of the more prevalent mutant substrains as the pandemic progressed. Episodes of COVID-19 illness later were reported to occur commonly in individuals who had been vaccinated with the newly developed vaccines in addition to many who had contracted the virus and previously experienced live infections early in the pandemic. ...
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  • May 2021
  • NATURE
The COVID-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. The prospects of ending this pandemic rest on the development of effective interventions. Single and combination monoclonal antibody (mAb) therapeutics have received emergency use authorization1–3, with more in the pipeline4–7. Furthermore, multiple vaccine constructs have shown promise8, including two with ~95% protective efficacy against COVID-199,10. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. The recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of the spike and relatively resistant to a few mAbs to the receptor-binding domain (RBD). It is not more resistant to convalescent plasma or vaccinee sera. Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple individual mAbs to the receptor-binding motif on RBD, largely owing to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4 fold) and vaccinee sera (10.3-12.4 fold). B.1.351 and emergent variants13,14 with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.
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SARS-CoV-2 mutations in MHC-I-restricted epitopes evade CD8 + T cell responses
Article
Full-text available
  • Mar 2021
CD8 ⁺ T cell immunity to SARS-CoV-2 has been implicated in COVID-19 severity and virus control. Here, we identified nonsynonymous mutations in MHC-I-restricted CD8 ⁺ T cell epitopes after deep sequencing of 747 SARS-CoV-2 virus isolates. Mutant peptides exhibited diminished or abrogated MHC-I binding in a cell-free in vitro assay. Reduced MHC-I binding of mutant peptides was associated with decreased proliferation, IFN-γ production and cytotoxic activity of CD8 ⁺ T cells isolated from HLA-matched COVID-19 patients. Single cell RNA sequencing of ex vivo expanded, tetramer-sorted CD8 ⁺ T cells from COVID-19 patients further revealed qualitative differences in the transcriptional response to mutant peptides. Our findings highlight the capacity of SARS-CoV-2 to subvert CD8 ⁺ T cell surveillance through point mutations in MHC-I-restricted viral epitopes.
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Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies
Article
Full-text available
  • Apr 2021
  • NAT MED
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.
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Negligible impact of SARS-CoV-2 variants on CD4 + and CD8 + T cell reactivity in COVID-19 exposed donors and vaccinees
Preprint
Full-text available
  • Mar 2021
The emergence of SARS-CoV-2 variants highlighted the need to better understand adaptive immune responses to this virus. It is important to address whether also CD4+ and CD8+ T cell responses are affected, because of the role they play in disease resolution and modulation of COVID-19 disease severity. Here we performed a comprehensive analysis of SARS-CoV-2-specific CD4+ and CD8+ T cell responses from COVID-19 convalescent subjects recognizing the ancestral strain, compared to variant lineages B.1.1.7, B.1.351, P.1, and CAL.20C as well as recipients of the Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) COVID-19 vaccines. Similarly, we demonstrate that the sequences of the vast majority of SARS-CoV-2 T cell epitopes are not affected by the mutations found in the variants analyzed. Overall, the results demonstrate that CD4+ and CD8+ T cell responses in convalescent COVID-19 subjects or COVID-19 mRNA vaccinees are not substantially affected by mutations found in the SARS-CoV-2 variants.
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mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants
Article
Full-text available
  • Apr 2021
  • NATURE
Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines1-4. Eight weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection5,6. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors5-8. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.
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Negligible impact of SARS-CoV-2 variants on CD4+and CD8+ T cell reactivity in COVID-19 exposed donors and vaccinees
  • A Tarke