Seasonal human coronavirus humoral responses in AZD1222 (ChaAdOx1 nCoV-19) COVID-19 vaccinated adults reveal limited cross-immunity

Abstract

Background: Immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now widespread; however, the degree of cross-immunity between SARS-CoV-2 and endemic, seasonal human coronaviruses (HCoVs) remains unclear.

Methods: SARS-CoV-2 and HCoV cross-immunity was evaluated in adult participants enrolled in a US sub-study in the phase III, randomized controlled trial (NCT04516746) of AZD1222 (ChAdOx1 nCoV-19) primary-series vaccination for one-year. Anti-HCoV spike-binding antibodies against HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63 were evaluated in participants following study dosing and, in the AZD1222 group, after a non-study third-dose booster. Timing of SARS-CoV-2 seroconversion (assessed via anti-nucleocapsid antibody levels) and incidence of COVID-19 were evaluated in those who received AZD1222 primary-series by baseline anti-HCoV titers.

Results: We evaluated 2,020/21,634 participants in the AZD1222 group and 1,007/10,816 in the placebo group. At the one-year data cutoff (March 11, 2022) mean duration of follow up was 230.9 (SD: 106.36, range: 1-325) and 94.3 (74.12, 1-321) days for participants in the AZD1222 (n = 1,940) and placebo (n = 962) groups, respectively. We observed little elevation in anti-HCoV humoral titers post study-dosing or post-boosting, nor evidence of waning over time. The occurrence and timing of SARS-CoV-2 seroconversion and incidence of COVID-19 were not largely impacted by baseline anti-HCoV titers.

Conclusion: We found limited evidence for cross-immunity between SARS-CoV-2 and HCoVs following AZD1222 primary series and booster vaccination. Susceptibility to future emergence of novel coronaviruses will likely persist despite a high prevalence of SARS-CoV-2 immunity in global populations.

Keywords: AZD1222 (ChaAdOx1 nCoV-19); COVID-19; COVID-19 vaccination; SARS-CoV-2; cross-immunity; human coronaviruses; humoral responses; seasonal coronavirus.

Figure 1

Anti-HCoV spike-binding antibody titers in participants over time for (A) HCoV-229E (B) HCoV-HKU1 (C) HCoV-NL63 (D) HCoV-OC43. Participants were censored on the date of the first reported instance of non-study COVID-19 vaccination. The bottom and top edges of the box indicate the first and third quartiles (the difference is the IQR) and the line inside the box is the median. The line connects the geometric mean value for every visit. Whiskers extending up to 1.5 times the IQR above the upper quartile and below the lower quartile. Any points more than 1.5 x IQR from the box were considered outliers and are not presented. The boxplots are presented in log2 scale. Baseline is defined as the last non-missing measurement taken prior to the first dose of study intervention (including unscheduled measurements, if any). Titer values measured as below LLoQ are imputed to half the LLoQ. Titer values measured as above ULoQ are imputed at the ULoQ value. Assessments collected after non-study COVID-19 vaccine administration/exclusionary restricted medication intake are excluded, regardless of unblinding. HCoV, human coronavirus, IQR, interquartile range, LLoQ, lower limit of quantification, ULoQ, upper limit of quantification.

Figure 2

Anti-HCoV spike-binding antibody titers at baseline in sub-study participants who received two doses of AZD1222, by post-treatment SARS-CoV-2 nucleocapsid serostatus. Post-treatment SARS-CoV-2 seropositivity was defined by the presence of an above threshold (>9787 AU mL-1) (35) response to SARS-CoV-2 nucleocapsid antibodies occurring ≥15 days after receiving a second dose of AZD1222. The bottom and top edges of the box indicate the first and third quartiles (the difference is the IQR), the line inside the box is the median, and the marker inside the box is the geometric mean. Any points more than 1.5 x IQR from the box were considered outliers and are not displayed. The whiskers that extend from the box indicate the minimum and maximum after removing the outliers. Boxplots are created using log transformed values. Titer values measured as below LLoQ are imputed to half the LLoQ. Titer values measured as above ULoQ are imputed at the ULoQ value. HCoV, human coronavirus, IQR, interquartile range, LLoQ, lower limit of quantification, ULoQ, upper limit of quantification, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3

Time to SARS-CoV-2 nucleocapsid seroconversion in post-treatment SARS-CoV-2 nucleocapsid seropositive sub-study participants who received two doses of AZD1222, by HCoV titer quartile at baseline for (A) HCoV-229E (B) HCoV-HKU1 (C) HCoV-NL63 (D) HCoV-OC43. Participants who received two doses of AZD1222 were sorted by HCoV titer at baseline with quartile one denoting participants with the lowest baseline titers and quartile four the highest baseline anti-HCoV spike-binding antibody titers. Post-treatment SARS-CoV-2 seropositivity was defined by the presence of an above threshold (>9787 AU mL^-1) (35) response to SARS-CoV-2 nucleocapsid antibodies occurring ≥15 days after receiving a second dose of AZD1222. The time to first post-treatment response has been calculated as follows: In days, the date of post-treatment response – (date of second dose of study intervention + 14) +1. For censored participants, the censoring time is from date of second dose of study intervention + 14, to last observed time during the analysis period/non-study COVID-19 vaccine administration. The bottom and top edges of the box indicate the first and third quartiles (the difference is the IQR), the line inside the box is the median, and the marker inside the box is the mean. Any points more than 1.5 x IQR from the box are considered outliers and are not displayed. The whiskers that extend from the box indicate the minimum and maximum after removing the outliers. Titer values measured as below LLoQ are imputed to half the LLoQ. Titer values measured as above ULoQ are imputed at the ULoQ value. HCoV, human coronavirus, IQR, interquartile range, LLoQ, lower limit of quantification, ULoQ, upper limit of quantification, SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 4

Cumulative incidence of post-treatment COVID-19 cases over time sub-study participants who received two doses of AZD1222, by baseline HCoV titer quartile for (A) HCoV-229E (B) HCoV-HKU1 (C) HCoV-NL63 (D) HCoV-OC43. Participants who received two doses of AZD1222 were sorted by HCoV titer at baseline with quartile one representing participants with the lowest baseline titers and quartile four the highest baseline anti-HCoV spike-binding antibody titers. Post-treatment COVID-19 cases were defined as those reported to occur ≥15 days after receiving a second dose of AZD1222. COVID-19 reported cases include any RT-PCR positive result or COVID-19 AEs, whichever occurred first. The time to first reported COVID-19 case was calculated as follows: in days, the date of reported COVID-19 – (date of receiving a second dose of study intervention + 14) + 1. For censored participants, the censoring time was defined as the date of second dose of study intervention + 14 up to the last study contact with the participant prior to the data cut-off/non-study COVID-19 vaccine administration. Participants who received a non-study COVID-19 vaccination prior to 15 days post second dose, or who did not have a baseline HCoV titer result, were excluded. The cumulative incidence curves are truncated at the point when less than 10% of participants remain at risk and active in the study, for each group. AE, adverse event, HCoV, human coronavirus, RT-PCR, reverse transcriptase polymerase chain reaction.