key: cord-0263223-n78ahii6
authors: Brunner, W. M.; Freilich, D. A.; Victory, J.; Krupa, N.; Scribani, M. B.; Jenkins, P.; Lasher, E. G.; Fink, A.; Shah, A.; Cross, P.; Bush, V.; Peek, L. J.; Pestano, G. A.; Gadomski, A. M.
title: Comparison of Antibody Response Durability of mRNA-1273, BNT162b2, and Ad26.COV2.S SARS-CoV-2 Vaccines in Healthcare Workers
date: 2022-01-15
journal: nan
DOI: 10.1101/2022.01.14.22269297
sha: a1dc2eb6960b50b7f5f02c52bd11abb81998a808
doc_id: 263223
cord_uid: n78ahii6

Importance: There is a dearth of comparative immunologic durability data after COVID-19 vaccinations. Objective: To compare antibody responses and vaccine effectiveness 8.4 months post-primary COVID-19 vaccination. Design, Setting and Participants: In this cohort study of 903 healthcare workers who completed surveys about baseline characteristics and COVID-19 vaccine/infection history, 647 had antibody assays completed and were included herein. Exposure: COVID-19 vaccination with mRNA-1273 (n=387); BNT162b2 (n=212); or Ad26.COV2.S (n=10); unvaccinated (n=10); or boosted (n=28). Main Outcomes and Measures: The primary outcome was IgG anti-spike titer. Secondary/tertiary outcomes included IgG spike receptor-binding domain competitive antibody blocking ELISA pseudoneutralization against the USA-WA1/2020 strain, and vaccine effectiveness against COVID-19 infection. Antibody levels were compared using ANOVA and multiple linear regression. Results: Mean age was 49.7, 75.3% were female, and mean comorbidities/patient was 0.7. Baseline variables were balanced (p>.05) except for immunosuppression (higher in boosted, p=.047), prior COVID-19 infections (higher with Ad26.COV2.S and unvaccinated, p<.001), and time since primary vaccination (higher with mRNA-1273 and BNT162b2 than Ad26.COV2.S, p<.001). Unadjusted median (IQR) IgG anti-spike titers (AU/mL) were 1539.5 (876.7-2626.7) for mRNA-1273, 751.2 (422.0-1381.5) for BNT162b2, 451.6 (103.0-2396.7) for Ad26.COV2.S, 113.4 (3.7-194.0) for unvaccinated, and 31898.8 (21347.1-45820.1) for boosted (mRNA-1273 vs. BNT162b2, p<.001; mRNA-1273, BNT162b2, or boosted vs. unvaccinated, p<.006; mRNA-1273, BNT162b2, Ad26.COV2.S, or unvaccinated vs. boosted, p<.001; all other comparisons, p>.05). Unadjusted median (IQR) pseudoneutralization percentages were 90.9% (80.1-95.0) for mRNA-1273, 77.2% (59.1-89.9) for BNT162b2, 57.9% (36.6-95.8) for Ad26.COV2.S, 40.1% (21.7-60.6) for unvaccinated, and 96.4% (96.1-96.6) for boosted (mRNA-1273 vs. BNT162b2, p<.001; mRNA-1273, BNT162b2, or boosted vs. unvaccinated, p<.028; mRNA-1273, BNT162b2, Ad26.COV2.S, or unvaccinated vs. boosted, p<.001; all other comparisons, p>.05). Adjusted anti-spike and pseudoneutralization comparisons of mRNA-1273 and BNT162b2 showed similar patterns (p<.001). Vaccine effectiveness was 87-89% for mRNA-1273, BNT162b2, and boosted, and 33% for Ad26.COV2.S; no group differences were statistically significant. Conclusions and Relevance: Durability of antibody responses 8.4 months after COVID-19 primary vaccination was significantly higher with mRNA-1273 than with BNT162b2, however, vaccine effectiveness was equivalent. Antibody responses and vaccine effectiveness were lower but not significantly different for Ad26.COV2.S; given statistical uncertainty in the small Ad26.COV2.S group, clinically important effects cannot be excluded.

To date, more than 820,000 Americans have died of COVID-19. Vaccination with FDA approved/authorized COVID-19 vaccines is imperative to control the pandemic. A number of studies have shown robust similar or higher early anti-spike (anti-S), anti-S-receptor binding domain (RBD), and neutralizing antibody (nAb) responses with mRNA-1273 than BNT162b2 and higher responses with both mRNA vaccines than Ad26.COV2.S. [1] [2] [3] [4] [5] [6] [7] The pattern for early vaccine effectiveness (VE) is similar, mRNA-1273 being about 90-95%, BNT162b2 about 90%, and Ad26.COV2.S about 70-85%, with lower and higher percentages being against infection and severe disease, respectively. 5, [8] [9] [10] [11] Individual durability studies for these vaccines have shown waning immunity over time, as measured by decreasing antibody titers and VE (breakthrough infections). 12- 34 The literature for comparative vaccine antibody durability, however, is limited. One study showed marked decreases in antibodies over [6] [7] [8] months for mRNA-1273 and BNT162b2 which contrasted with relatively durable responses for Ad26.COV2.S; because responses to Ad26.COV2.S were lower early post-vaccination, antibody responses were comparable at 6-8 months. 3 Another comparative antibody durability study showed 3fold decreases in anti-S and anti-S-RBD antibody titers from peak post-vaccination (14-119 days) to >120 days with mRNA-1273 and BNT162b2, but mRNA-1273 titers were 3-fold higher at both time points. 35 Numerous comparative VE durability studies, occurring at different pandemic stages with differing prevalent strains, showed decreases to 80-95% at 3-7 months for mRNA-1273, 65-90% for BNT162b2, and 60-70% for Ad26.COV2.S. 5, 10, 11, [35] [36] [37] [38] Due to the dearth of comparative vaccine durability studies, particularly for antibody responses, we sought to compare medium range durability (at 8. 

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint This observational cohort study is a follow-up to a seroprevalence study conducted among Bassett Healthcare Network HCWs in May-August 2020 (IRB#1597947). 39 Primary steps included securing consent, online surveys, blood drawing/processing, and antibody assays. The Mary Imogene Bassett IRB approved this follow-up as an amendment to the original study.

HCWs were eligible for this follow-up study if they consented to storage of their plasma samples for . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint Anti-S antibody tests were performed by Bassett Medical Center's Laboratory using the Abbott AdviseDx SARS-CoV-2 IgG II semi-quantitative assay with dilution if necessary (Abbott Laboratories, Abbott Park, IL). Anti-N antibody tests were also performed by Bassett's laboratory using the SARS-CoV-2 IgG Abbott Architect assay (Abbott Laboratories, Abbott Park, IL). 40 Neutralization antibodies to spike protein RBD were measured using ELISA-based pseudoneutralization (competitive antibody blocking) COVID-19 assays (cPASS TM , GenScript, Piscataway, NJ) using USA-WA1/2020 strain genetic background and were performed by Biodesix (Boulder, CO). The α-RBD nAb test measures a subset of antibodies that can block the interaction between the RBD on the SARS-CoV-2 spike protein and the human host receptor angiotensin-converting enzyme 2 (ACE2). Methods for the cPASS surrogate virus neutralization test (SVNT) were previously published, validated, and shown to be 100% sensitive and specific when compared to gold standard, plaque reduction neutralization test (PRNT), with qualitative analysis results 100% in agreement. [41] [42] [43] [44] The nAb assay readout was percent signal inhibition by neutralizing antibodies, calculated as the optical density (OD) value of the sample relative to the OD of the negative control subtracted from one. 42 The cPASS assay has an EUA for qualitative interpretation of results, 41 but here we prioritize presenting numeric semi-quantitative percent signal inhibition to compare between-group percentages.

Outcome variables were compared by five prespecified characteristics thought to impact immune responses to COVID-19 vaccination: age, number of comorbidities, immunosuppression, time from completion of primary vaccination (days), and prior COVID-19 infection.

Categorical variables were compared between groups using chi-square. Fisher's exact test was used with small cell sizes. Continuous variables were compared using one-by-five analysis of variance (ANOVA). For certain continuous variables with skewed distributions, including time from primary vaccination and pseudoneutralization percentages, we were unable to find a suitable transformation of the data to achieve normality. Therefore, data were converted to ranks prior to being analyzed using ANOVA. For anti-S titers, it was found that a natural log transformation resulted in a normal distribution that could be analyzed in the ANOVA model. Post-hoc tests were performed using Scheffe's method.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint A second set of analyses comparing only mRNA-1273 and BNT162b2 groups was completed. In addition to the main effect of vaccine group, these analyses included an additional dimension for the previously mentioned covariates. Multiple linear regression was also performed on the natural log of anti-S titers and the ranks of the pseudoneutralization percentages, including adjustment for covariates. Age, comorbidities, and time since vaccination were modeled as continuous variables.

Spearman's correlation coefficients were calculated for anti-S levels and pseudoneutralization percentages. VE was estimated by calculating ((infection rate among the unvaccinated -the infection rate among the vaccinated)/infection rate among the unvaccinated))*100.

Missing data on key variables (COVID-19 infection status, vaccination dates, immunosuppression) were either confirmed directly with study subjects or via medical record review. Other missing values were left as missing; imputation of missing values not conducted. Statistical significance was defined as p<.05.

All statistical analyses were performed using SAS version 9.4 (Cary, NC).

Mean age was 49.7, 75.3% were female, 93.5% were white, mean number of comorbidities was 0.7/patient, 4.3% had immunosuppression, and median interval from completion of primary vaccination to blood drawing was 255 days (8.4 months). Baseline variables were balanced by age, sex, race, and comorbidities (p>.05), not immunosuppression (p=.047), prior COVID-19 infection (p<.001), time since vaccination (p<.001), and vaccine choice (p<.001) ( Table 1) .

Among the 28 boosted HCWs, 19 (67.9%) received BNT162b2 (primary)-BNT162b2 (booster), 5 (17.9%) mRNA-1273-mRNA-1273 3 rd dose, 2 (7.1%) mRNA-1273-mRNA-1273 booster, and 2 (7.1%) mRNA-1273-BNT162b2. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint p<.006; Groups 1, 2, 3, or 4 vs. 5, p<.001; all other comparisons, p>.05) (Table 2/ Figure 1) . In multivariable analysis, adjusted median anti-S titers for Groups 1 and 2 remained significantly different (p<.001) ( Table 3 ). All covariates were independently associated with anti-S titers except for number of comorbidities (p=.93).

Unadjusted median (IQR) pseudoneutralization signal inhibition percentages were highest in Group 5 Table 2 ). In multivariable analysis, adjusted median pseudoneutralization percentages for Groups 1 and 2 remained significantly different (p<.001). Time since vaccination and age were significantly associated with lower percentages (p<.001). Previous infection was associated with higher percentages (p<.001). Immunosuppression (p=.51) and comorbidities (p=.63) were not associated with pseudoneutralization.

COVID-19 infection rates as measured by anti-N antibody and/or clinical laboratory-confirmed COVID-19 infection data during this ~8.4-month period were 3.4% (13/387) in Group 1, 3.8% (8/212) in Group 2, 20% (2/10) in Group 3, 30% (3/10) in Group 4, and 3.6% (1/38) in Group 5 (overall, p=.004; Groups 1, 2, or 5 vs. 4, p<.05; Group 1 vs. 3, p=.05; Group 2 vs. 3, p=.07; all other comparisons, p>.10). All were treated as outpatients (no hospitalizations or deaths). Estimated VE rates were 89% (95% CI 67%-96%) in Group 1, 87% (95% CI 60%-96%) in Group 2, 33% (95% CI 0%-86%) in Group 3, and 88% (95% CI 0%-99%) in Group 5. Most breakthrough infections were in summer/fall 2021, suggesting Delta variant infections (eFigure 2).

Stratification by age showed different effects by vaccine type on anti-S antibody titers and pseudoneutralization percentages at 8.4 months, with older HCWs having significantly lower responses than younger HCWs for BNT162b2 (p=.002) but not mRNA-1273 (p=.40). Stratification by number of comorbidities, immunosuppression status, and time from primary vaccination did not show significant differences. However, stratification by prior COVID-19 infection status showed significant effects on . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint anti-S antibody titers and pseudoneutralization percentages for both mRNA-1273 and BNT162b2 (p<.001 for all comparisons) ( Table 2) .

Correlation for anti-S antibody titers and pseudoneutralization percentages in the overall population was high (ρ=.947, p<.001). Correlation coefficients were .926, .934, .903, .867, and .397 for Groups 1 through 5, respectively (all p<.05).

This COVID-19 vaccine comparative immune response durability cohort study showed that medium range antibody responses at a median of 8.4 months after primary vaccination were higher after vaccination with mRNA-1273 than BNT162b2. Ad26.COV2.S antibody responses were lower but not significantly different than with mRNA-1273 and BNT162b2. Specifically, both median IgG spike protein . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. 7, 13 suggesting that primary vaccination with mRNA-1273 rather than BNT162b2 should be prioritized for older individuals. We did not complete subgroup analyses for VE precluding assessment of such an age effect. BNT162b2 antibody studies show high antibody titers (same specific antibodies as above) postvaccination that wane by 2-6 months (more rapidly in immunosuppressed adults), and increase with . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint boosting. [16] [17] [18] [19] [20] [21] [22] [23] [24] VE studies show high protection against infection with durability for 6 months (90-95%) earlier in the pandemic when Alpha and Beta variants predominated, but with waning to as low as 20% later when Beta and Delta variants predominated; VE against severe disease (hospitalization and death) remained high (>90%) throughout the pandemic. [29] [30] [31] 34 VE against infection, severe infection, and mortality in Israel when Delta predominated was much higher with boosting. 49, 50 Ad26.COV2.S antibody studies show high titers post-vaccination (albeit lower than with both mRNA vaccines) that are relatively durable for 8 months (only 1.8-fold decrease). 25, 26 VE studies show protection against infection and severe disease of 64-85% after vaccination. 33, 51 Comparative antibody studies, soon after primary vaccination, show titers that are similar or higher for mRNA-1273 vs. BNT162b2 and higher with either vs. Ad26.COV2.S. [1] [2] [3] [4] [5] [6] [7] One of two comparative antibody durability studies showed marked decreases in anti-S-RBD and nAb titers for mRNA-1273 and BNT162b2 at 6-8 months. In that study, Ad26.COV2.S's initially lower titers were more durable such that by 6-8 months titers were similar between the three vaccines. 3 Another study showed about 3-fold higher peak (14-119 days) anti-S and anti-S-RBD titers with mRNA-1273 vs. BNT162b2 with similar 3-fold decreases after 4 months, such that after 4 months, both antibody levels remained 3-fold higher with mRNA-1273. 35 Likewise, our results show significantly higher anti-S titers and pseudoneutralization percentages at 8.4 months for mRNA-1273 vs. BNT162b2, and higher (but not significantly different) results for mRNA-1273 and BNT162b2 vs. Ad26.COV2.S. However, we cannot make conclusions about relative diminution of these titers as we did not complete sequential antibody assays.

Comparative VE studies show higher protection against infection and hospitalization for mRNA-1273 (90-95%) and BNT162b2 (90%) than for Ad26.COV2.S (70-85%) post-vaccination. 5, [8] [9] [10] [11] Comparative VE durability studies against infection and severe disease at different pandemic times show waning to 80-95% for mRNA-1273, 65-90% by 3-7 months for BNT162b2, and 60-70% for Ad26.COV2.S; 5, 10, 11, 36-38 the higher ranges were for VE against more severe disease for all three vaccines. In contrast, our study showed equivalently high VE against infection at 8.4 months (87-89%) with mRNA-1273 and BNT162b2 despite significantly higher anti-S titers and pseudoneutralization percentages with mRNA-1273 than BNT162b2; VE was higher but not significantly different with both mRNA vaccines than with Ad26.COV2.S (33%).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint Key study limitations included the following: (1) Our study was observational. We addressed predicted confounders by adjusting for covariates likely to impact results; however, unmeasured confounders 5) The study design (with addition of the boosted group) and statistical analysis plan (primary analysis focused on subpopulation of surveyed participants) were modified after initiation of enrollment; however, these changes were prespecified prior to seeing primary outcome data. (6) The boosted group included varying primary vaccination-boosting combinations although BNT162b2-BNT162b2 was predominant (67.9%); and insufficient follow-up time to assess boosting's effects on VE. (7) Antibody inhibition pseudoneutralization assays were completed rather than gold standard PRNT; however, good correlation has been reported for these tests. 44 

In this COVID-19 vaccines comparative immunology durability cohort study, at a median of 8.4 months after primary vaccination, IgG spike protein antibody titers and pseudoneutralization inhibition percentages against SARS-CoV-2 USA-WA1/2020 were significantly higher with mRNA-1273 than with BNT162b, both of which were not significantly higher than with Ad26.COV2.S. Vaccine effectiveness against infection remained high with both mRNA vaccines (87-89%), also being higher but not significantly different than with Ad26.COV2.S (33%). Due to statistical uncertainty in the small Ad26.COV2.S group, clinically meaningful outcomes differences cannot be excluded. Boosting led to dramatic increases in anti-S and pseudoneutralization responses.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 15, 2022. ; https://doi.org/10.1101/2022.01.14.22269297 doi: medRxiv preprint 

Boxplots showing antibody levels by study group at a median of 8.4 months since complete vaccination. The bar inside each box represents the median and the diamond represents the mean antibody level. A, Difference in unadjusted log-anti-S antibodies by vaccine type. B, Difference in unadjusted pseudoneutralization signal inhibition percentages by vaccine type. Note: Sixty percent (6/10) of the unvaccinated HCWs reported a COVID-19 infection prior to antibody testing.

Unadjusted pseudoneutralization signal inhibition (cPASS) B Unadjusted log-anti-S titers A

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Other" race indicates the HCW provided a response different from the five categories

Laboratory-confirmed infection was based on medical record evidence of a positive PCR test or a positive anti-N antibody test from the original 2020 or this follow-up study. e Response to survey question

We would like to thank the Bassett Research Institute Center for Clinical Research staff (Melissa Huckabone, Martina King, and Catherine Gilmore) and Casie Collins (New York Center for Agricultural Medicine and Health) for completing the blood draws, the Bassett Healthcare Network Clinical