The Four Ws of the Fourth Dose COVID-19 Vaccines: Why, Who, When and What

doi:10.3390/vaccines10111924

Review

. 2022 Nov 14;10(11):1924.

doi: 10.3390/vaccines10111924.

The Four Ws of the Fourth Dose COVID-19 Vaccines: Why, Who, When and What

Ka-Wa Khong¹, Ruiqi Zhang¹, Ivan Fan-Ngai Hung^{1

2

3}

Affiliations

¹ Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
² State Key Laboratory for Emerging Infectious Disease, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
³ Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.

PMID: 36423020
PMCID: PMC9694140
DOI: 10.3390/vaccines10111924

Review

The Four Ws of the Fourth Dose COVID-19 Vaccines: Why, Who, When and What

Ka-Wa Khong et al. Vaccines (Basel). 2022.

. 2022 Nov 14;10(11):1924.

doi: 10.3390/vaccines10111924.

Authors

Ka-Wa Khong¹, Ruiqi Zhang¹, Ivan Fan-Ngai Hung^{1

2

3}

Affiliations

¹ Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
² State Key Laboratory for Emerging Infectious Disease, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
³ Carol Yu Centre for Infection, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.

PMID: 36423020
PMCID: PMC9694140
DOI: 10.3390/vaccines10111924

Abstract

With the emergence of SARS-CoV-2 variants, vaccine breakthrough is a major public health concern. With evidence of reduced neutralizing antibody activity against Omicron variants and fading antibody level after the third-dose booster vaccine, there are suggestions of a fourth-dose booster vaccine. In this review, the benefits of a fourth-dose booster is evaluated from four perspectives, including the effectiveness of the booster dose against virus variants (Why), susceptible groups of individuals who may benefit from additional booster dose (Who), selection of vaccine platforms to better enhance immunity (What) and appropriate intervals between the third and fourth booster dose (When). In summary, a fourth dose can temporarily boost the immune response against SARS-CoV-2 variants and can be considered for specific groups of individuals. A heterologous vaccine strategy using mRNA vaccine in individuals primed with inactivated vaccine may boost immunity against variants. The timing of the fourth dose should be individualized but an interval of 4 months after the third-dose booster is appropriate. A universal fourth booster dose is not necessary.

Keywords: COVID-19 vaccine; Omicron variant; booster dose.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 2**
Changes in serum antibodies after vaccination or infection in different patient groups. Elderly patients may have a poorer response to vaccination and lower titre of serum-neutralizing antibodies after vaccination [33,37,38]. Immunocompromised patients, especially patients with solid organ transplants, may have suboptimal response to vaccination with a low level of neutralizing antibodies or being seronegative after the third and fourth booster doses [40,41,51,52,53]. Individuals who were infected before vaccination or have breakthrough infection after vaccination were demonstrated to have a higher level of neutralizing antibodies [56,57].

**Figure 1**
Changes in serum-neutralizing antibodies against SARS-CoV-2 Wild-Type virus and Omicron variant with time. Vaccine efficacy started to decline 2–4 months after the third-dose booster [13]. After third-dose booster, level of neutralizing antibodies against Omicron variant was lower than that against other strains such Wild-Type, Beta and Delta variants [8,15,16]. Furthermore, the response to the fourth-dose booster was comparable to the third-dose booster [22,23].

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References

1. Seow J., Graham C., Merrick B., Acors S., Pickering S., Steel K.J.A., Hemmings O., O’Byrne A., Kouphou N., Galao R.P., et al. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat. Microbiol. 2020;5:1598–1607. doi: 10.1038/s41564-020-00813-8. - DOI - PMC - PubMed
1. Thakur V., Ratho R.K. OMICRON (B.1.1.529): A new SARS-CoV-2 variant of concern mounting worldwide fear. J. Med. Virol. 2022;94:1821–1824. doi: 10.1002/jmv.27541. - DOI - PubMed
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1. Carreño J.M., Alshammary H., Tcheou J., Singh G., Raskin A.J., Kawabata H., Sominsky L.A., Clark J.J., Adelsberg D.C., Bielak D.A., et al. Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron. Nature. 2022;602:682–688. doi: 10.1038/s41586-022-04399-5. - DOI - PubMed
1. Lu L., Mok B.W., Chen L.L., Chan J.M., Tsang O.T., Lam B.H., Chuang V., Chu A., Chan W.M., Ip J.D., et al. Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients. Clin. Infect. Dis. 2022;75:e822–e826. doi: 10.1093/cid/ciab1041. - DOI - PMC - PubMed

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[1] Seow J., Graham C., Merrick B., Acors S., Pickering S., Steel K.J.A., Hemmings O., O’Byrne A., Kouphou N., Galao R.P., et al. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat. Microbiol. 2020;5:1598–1607. doi: 10.1038/s41564-020-00813-8. - DOI - PMC - PubMed

[2] Seow J., Graham C., Merrick B., Acors S., Pickering S., Steel K.J.A., Hemmings O., O’Byrne A., Kouphou N., Galao R.P., et al. Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans. Nat. Microbiol. 2020;5:1598–1607. doi: 10.1038/s41564-020-00813-8. - DOI - PMC - PubMed

[3] Thakur V., Ratho R.K. OMICRON (B.1.1.529): A new SARS-CoV-2 variant of concern mounting worldwide fear. J. Med. Virol. 2022;94:1821–1824. doi: 10.1002/jmv.27541. - DOI - PubMed

[4] Thakur V., Ratho R.K. OMICRON (B.1.1.529): A new SARS-CoV-2 variant of concern mounting worldwide fear. J. Med. Virol. 2022;94:1821–1824. doi: 10.1002/jmv.27541. - DOI - PubMed

[5] Planas D., Saunders N., Maes P., Guivel-Benhassine F., Planchais C., Buchrieser J., Bolland W.H., Porrot F., Staropoli I., Lemoine F., et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2022;602:671–675. doi: 10.1038/s41586-021-04389-z. - DOI - PubMed

[6] Planas D., Saunders N., Maes P., Guivel-Benhassine F., Planchais C., Buchrieser J., Bolland W.H., Porrot F., Staropoli I., Lemoine F., et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature. 2022;602:671–675. doi: 10.1038/s41586-021-04389-z. - DOI - PubMed

[7] Carreño J.M., Alshammary H., Tcheou J., Singh G., Raskin A.J., Kawabata H., Sominsky L.A., Clark J.J., Adelsberg D.C., Bielak D.A., et al. Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron. Nature. 2022;602:682–688. doi: 10.1038/s41586-022-04399-5. - DOI - PubMed

[8] Carreño J.M., Alshammary H., Tcheou J., Singh G., Raskin A.J., Kawabata H., Sominsky L.A., Clark J.J., Adelsberg D.C., Bielak D.A., et al. Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron. Nature. 2022;602:682–688. doi: 10.1038/s41586-022-04399-5. - DOI - PubMed

[9] Lu L., Mok B.W., Chen L.L., Chan J.M., Tsang O.T., Lam B.H., Chuang V., Chu A., Chan W.M., Ip J.D., et al. Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients. Clin. Infect. Dis. 2022;75:e822–e826. doi: 10.1093/cid/ciab1041. - DOI - PMC - PubMed

[10] Lu L., Mok B.W., Chen L.L., Chan J.M., Tsang O.T., Lam B.H., Chuang V., Chu A., Chan W.M., Ip J.D., et al. Neutralization of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients. Clin. Infect. Dis. 2022;75:e822–e826. doi: 10.1093/cid/ciab1041. - DOI - PMC - PubMed

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The Four Ws of the Fourth Dose COVID-19 Vaccines: Why, Who, When and What

Affiliations

The Four Ws of the Fourth Dose COVID-19 Vaccines: Why, Who, When and What

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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Cited by

References

Publication types

Grants and funding

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