Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant-dependent manner

doi:10.1016/j.chom.2021.10.003

. 2021 Nov 10;29(11):1611-1619.e5.

doi: 10.1016/j.chom.2021.10.003. Epub 2021 Oct 13.

Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant-dependent manner

Roanne Keeton¹, Simone I Richardson², Thandeka Moyo-Gwete², Tandile Hermanus², Marius B Tincho¹, Ntombi Benede¹, Nelia P Manamela², Richard Baguma³, Zanele Makhado², Amkele Ngomti¹, Thopisang Motlou², Mathilda Mennen⁴, Lionel Chinhoyi⁴, Sango Skelem⁴, Hazel Maboreke⁵, Deelan Doolabh¹, Arash Iranzadeh¹, Ashley D Otter⁶, Tim Brooks⁶, Mahdad Noursadeghi⁷, James C Moon⁸, Alba Grifoni⁹, Daniela Weiskopf⁹, Alessandro Sette¹⁰, Jonathan Blackburn⁵, Nei-Yuan Hsiao¹¹, Carolyn Williamson¹², Catherine Riou¹², Ameena Goga¹³, Nigel Garrett¹⁴, Linda-Gail Bekker¹⁵, Glenda Gray¹³, Ntobeko A B Ntusi¹⁶, Penny L Moore¹⁷, Wendy A Burgers¹⁸

Affiliations

¹ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
² National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa; MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
³ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
⁴ Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa.
⁵ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
⁶ National Infection Service, Public Health England, Porton Down, UK.
⁷ Division of Infection and Immunity, University College London, London, UK.
⁸ Institute of Cardiovascular Sciences, University College London, London, UK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
⁹ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA.
¹⁰ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, CA, USA.
¹¹ Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa; NHLS Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
¹² Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa.
¹³ South African Medical Research Council, Cape Town, South Africa.
¹⁴ Centre for the AIDS Programme of Research in South Africa, Durban, South Africa; Discipline of Public Health Medicine, University of KwaZulu-Natal, Durban, South Africa.
¹⁵ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Desmond Tutu HIV Centre, Cape Town, South Africa.
¹⁶ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa; Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. Electronic address: ntobeko.ntusi@uct.ac.za.
¹⁷ National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa; MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: pennym@nicd.ac.za.
¹⁸ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa. Electronic address: wendy.burgers@uct.ac.za.

PMID: 34688376
PMCID: PMC8511649
DOI: 10.1016/j.chom.2021.10.003

Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant-dependent manner

Roanne Keeton et al. Cell Host Microbe. 2021.

. 2021 Nov 10;29(11):1611-1619.e5.

doi: 10.1016/j.chom.2021.10.003. Epub 2021 Oct 13.

Authors

Affiliations

¹ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
² National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa; MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
³ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
⁴ Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa.
⁵ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa.
⁶ National Infection Service, Public Health England, Porton Down, UK.
⁷ Division of Infection and Immunity, University College London, London, UK.
⁸ Institute of Cardiovascular Sciences, University College London, London, UK; Barts Heart Centre, St Bartholomew's Hospital, Barts Health NHS Trust, London, UK.
⁹ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA.
¹⁰ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA; Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California San Diego, La Jolla, CA, USA.
¹¹ Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa; NHLS Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
¹² Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa.
¹³ South African Medical Research Council, Cape Town, South Africa.
¹⁴ Centre for the AIDS Programme of Research in South Africa, Durban, South Africa; Discipline of Public Health Medicine, University of KwaZulu-Natal, Durban, South Africa.
¹⁵ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Desmond Tutu HIV Centre, Cape Town, South Africa.
¹⁶ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa; Hatter Institute for Cardiovascular Research in Africa, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. Electronic address: ntobeko.ntusi@uct.ac.za.
¹⁷ National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa; MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa. Electronic address: pennym@nicd.ac.za.
¹⁸ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Cape Town, South Africa. Electronic address: wendy.burgers@uct.ac.za.

PMID: 34688376
PMCID: PMC8511649
DOI: 10.1016/j.chom.2021.10.003

Abstract

The Johnson and Johnson Ad26.COV2.S single-dose vaccine represents an attractive option for coronavirus disease 2019 (COVID-19) vaccination in countries with limited resources. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus or infected in the second wave when Beta predominated. Prior infection significantly boosts spike-binding antibodies, antibody-dependent cellular cytotoxicity, and neutralizing antibodies against D614G, Beta, and Delta; however, neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses are induced after vaccination, regardless of prior infection. T cell recognition of variants is largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination after infection could result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.

Keywords: Ad26CoV2.S; Fc effector function; SARS-CoV-2; hybrid immunity; neutralization; vaccines; variants of concern.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests A.S. is a consultant for Gritstone, Flow Pharma, CellCarta, Arcturus, Oxford Immunotech, and Avalia. All of the other authors declare no competing interests. LJI has filed for patent protection for various aspects of vaccine design and identification of specific epitopes.

Figures

**Figure 1**
Spike-specific antibody responses in Ad26.COV2.S-vaccinated healthcare workers (A) Study design showing three groups (left panel), either with no prior infection or infection in the first wave (May–August 2020) and infection in the second wave (November 2020–January 2021). Samples were taken pre-vaccination and one month after vaccination. SARS-CoV-2 epidemiological dynamics in the Western Cape (South Africa) are shown (top right panel). Prevalence of SARS-CoV-2 lineages is shown on the left y axis. The ancestral strain (D614G) is depicted in blue, and Beta is depicted in red. The number of COVID-19 cases is represented on the right y axis. The bars on top of the graph indicate the periods when participants were infected in the first and second waves. Vertical dotted lines indicate when vaccination occurred. Characteristics of participants in the three groups (bottom right panel). Sex, age (median and IQR), and days since PCR-confirmed infection. (B) Plasma samples from participants with no prior infection (green, n = 19), first-wave infection (blue, n = 20), or second-wave infection (red, n = 19) were tested for binding to D614G spike protein pre- and post-vaccination (OD_450nm). (C) Cross-reactivity of vaccine-induced antibody responses to D614G and Beta spike. The colored lines below the graph correspond with the key. The threshold for positivity is indicated by a dotted line. Horizontal bars indicate GMT, with values shown. Statistical analyses were performed with the Mann-Whitney test between groups, and the Wilcoxon test was performed for pre- and post-vaccine time points or D614G in comparison with Beta responses. ^∗∗∗p < 0.001.

**Figure 2**
Neutralizing antibody responses to Ad26.COV2.S vaccination (A) Neutralization of the SARS-CoV-2 D614G pseudovirus by plasma pre- and post-vaccination from participants with no prior infection (green, n = 19) and those infected in the first (blue, n = 20) and second waves (red, n = 19). Neutralization is reflected as an ID₅₀ titer. The threshold for positivity is indicated by a dotted line (B) Cross-reactive neutralization post-vaccination against D614G, Beta, and Delta. Pie charts show the proportion of vaccine non-responders (NR; gray), knockout of neutralization of Beta or Delta (KO; black), and the titer of 20–400 (orange), or >400 (red). The horizontal bars indicate GMT, with values indicated. Statistical analyses were performed with the Friedman test between groups and the Wilcoxon test for paired analyses. ^∗p < 0.05, ^∗∗∗p < 0.001. (C) Fold change of post-vaccination D614G neutralization titers relative to Beta or Delta. The vertical bars indicate median fold change with error bars for IQR.

**Figure 3**
ADCC responses to Ad26.COV2.S vaccination (A) ADCC activity represented as relative light units (RLU). (B) Cross-reactive ADCC activity 28 days post-vaccination against D614G, Beta, and Delta. Pie charts show the proportion of vaccine non-responders (NR; gray), knockout of Beta/Delta neutralization (KO; black), or detectable ADCC activity (41–150, orange; >150, red). Statistical analyses were performed with the Friedman test between groups and the Wilcoxon test for pre- and post-vaccine time points or D614G in comparison with Beta/Delta responses. ^∗p < 0.05, ^∗∗p < 0.01, ^∗∗∗p < 0.001. (C) Fold change of post-vaccination D614G ADCC levels relative to those of the Beta/Delta variants. The vertical bars indicate median fold difference and error bars the IQR.

**Figure 4**
T cell responses to Ad26.COV2.S vaccination (A and B) Frequency of total cytokine-producing spike-specific CD4 T cells (A) and CD8 T cells (B) in those with no prior infection (green, n = 19), infection in the first wave (blue, n = 20), and infection in the second wave (red, n = 19), in PBMCs stimulated with peptides based on Wuhan spike. (C) Median fold change of CD4 and CD8 T cell frequencies after vaccination in responders. Error bars indicate IQR. Pie charts show responders (black) and non-responders (gray), with the percentage of responders indicated. (D) Cross-reactivity of T cell responses post-vaccination (n = 24) after peptide stimulation with spike from the ancestral strain, Beta, or Delta is shown. Horizontal bars indicate medians. The dotted line indicates the threshold for positivity and values are background subtracted. Statistical analyses were performed with the Wilcoxon test. ^∗p < 0.05, ^∗∗p < 0.01.

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References

1. Alter G., Yu J., Liu J., Chandrashekar A., Borducchi E.N., Tostanoski L.H., McMahan K., Jacob-Dolan C., Martinez D.R., Chang A., et al. Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans. Nature. 2021;596:268–272. doi: 10.1038/s41586-021-03681-2. - DOI - PMC - PubMed
1. Barouch D.H., Stephenson K.E., Sadoff J., Yu J., Chang A., Gebre M., McMahan K., Liu J., Chandrashekar A., Patel S., et al. Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination. N. Engl. J. Med. 2021;385:951–953. doi: 10.1056/NEJMc2108829. - DOI - PMC - PubMed
1. Braun J., Loyal L., Frentsch M., Wendisch D., Georg P., Kurth F., Hippenstiel S., Dingeldey M., Kruse B., Fauchere F., et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020;587:270–274. doi: 10.1038/s41586-020-2598-9. - DOI - PubMed
1. Cele S., Gazy I., Jackson L., Hwa S.H., Tegally H., Lustig G., Giandhari J., Pillay S., Wilkinson E., Naidoo Y., et al. Network for Genomic Surveillance in South Africa. COMMIT-KZN Team Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. Nature. 2021;593:142–146. doi: 10.1038/s41586-021-03471-w. - DOI - PMC - PubMed
1. Cleemput S., Dumon W., Fonseca V., Abdool Karim W., Giovanetti M., Alcantara L.C., Deforche K., de Oliveira T. Genome Detective Coronavirus Typing Tool for rapid identification and characterization of novel coronavirus genomes. Bioinformatics. 2020;36:3552–3555. doi: 10.1093/bioinformatics/btaa145. - DOI - PMC - PubMed

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[1] Alter G., Yu J., Liu J., Chandrashekar A., Borducchi E.N., Tostanoski L.H., McMahan K., Jacob-Dolan C., Martinez D.R., Chang A., et al. Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans. Nature. 2021;596:268–272. doi: 10.1038/s41586-021-03681-2. - DOI - PMC - PubMed

[2] Alter G., Yu J., Liu J., Chandrashekar A., Borducchi E.N., Tostanoski L.H., McMahan K., Jacob-Dolan C., Martinez D.R., Chang A., et al. Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans. Nature. 2021;596:268–272. doi: 10.1038/s41586-021-03681-2. - DOI - PMC - PubMed

[3] Barouch D.H., Stephenson K.E., Sadoff J., Yu J., Chang A., Gebre M., McMahan K., Liu J., Chandrashekar A., Patel S., et al. Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination. N. Engl. J. Med. 2021;385:951–953. doi: 10.1056/NEJMc2108829. - DOI - PMC - PubMed

[4] Barouch D.H., Stephenson K.E., Sadoff J., Yu J., Chang A., Gebre M., McMahan K., Liu J., Chandrashekar A., Patel S., et al. Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination. N. Engl. J. Med. 2021;385:951–953. doi: 10.1056/NEJMc2108829. - DOI - PMC - PubMed

[5] Braun J., Loyal L., Frentsch M., Wendisch D., Georg P., Kurth F., Hippenstiel S., Dingeldey M., Kruse B., Fauchere F., et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020;587:270–274. doi: 10.1038/s41586-020-2598-9. - DOI - PubMed

[6] Braun J., Loyal L., Frentsch M., Wendisch D., Georg P., Kurth F., Hippenstiel S., Dingeldey M., Kruse B., Fauchere F., et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature. 2020;587:270–274. doi: 10.1038/s41586-020-2598-9. - DOI - PubMed

[7] Cele S., Gazy I., Jackson L., Hwa S.H., Tegally H., Lustig G., Giandhari J., Pillay S., Wilkinson E., Naidoo Y., et al. Network for Genomic Surveillance in South Africa. COMMIT-KZN Team Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. Nature. 2021;593:142–146. doi: 10.1038/s41586-021-03471-w. - DOI - PMC - PubMed

[8] Cele S., Gazy I., Jackson L., Hwa S.H., Tegally H., Lustig G., Giandhari J., Pillay S., Wilkinson E., Naidoo Y., et al. Network for Genomic Surveillance in South Africa. COMMIT-KZN Team Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. Nature. 2021;593:142–146. doi: 10.1038/s41586-021-03471-w. - DOI - PMC - PubMed

[9] Cleemput S., Dumon W., Fonseca V., Abdool Karim W., Giovanetti M., Alcantara L.C., Deforche K., de Oliveira T. Genome Detective Coronavirus Typing Tool for rapid identification and characterization of novel coronavirus genomes. Bioinformatics. 2020;36:3552–3555. doi: 10.1093/bioinformatics/btaa145. - DOI - PMC - PubMed

[10] Cleemput S., Dumon W., Fonseca V., Abdool Karim W., Giovanetti M., Alcantara L.C., Deforche K., de Oliveira T. Genome Detective Coronavirus Typing Tool for rapid identification and characterization of novel coronavirus genomes. Bioinformatics. 2020;36:3552–3555. doi: 10.1093/bioinformatics/btaa145. - DOI - PMC - PubMed

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Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant-dependent manner

Affiliations

Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant-dependent manner

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Abstract

Conflict of interest statement

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