Effectiveness of MRNA booster vaccine among healthcare workers in New York City during the Omicron surge, December 2021 to January 2022.

OBJECTIVE: To describe effectiveness of mRNA vaccines by comparing 2-dose (2D) and 3-dose (3D) healthcare worker (HCW) recipients in the setting of Omicron variant dominance. Performance of 2D and 3D vaccine series against SARS-CoV-2 variants and the clinical outcomes of HCWs may inform return-to-work guidance.
METHODS: In a retrospective study from December 15, 2020 to January 15, 2022, SARS-CoV-2 infections among HCWs at a large tertiary cancer centre in New York City were examined to estimate infection rates (aggregated positive tests / person-days) and 95% CIs over the Omicron period in 3D and 2D mRNA vaccinated HCWs and were compared using rate ratios. We described the clinical features of post-vaccine infections and impact of prior (pre-Omicron) COVID infection on vaccine effectiveness.
RESULTS: Among the 20857 HCWs in our cohort, 20,660 completed the 2D series with an mRNA vaccine during our study period and 12461 had received a third dose by January 15, 2022. The infection rate ratio for 3D versus 2D vaccinated HCWs was 0.667 (95% CI 0.623, 0.713) for an estimated 3D vaccine effectiveness of 33.3% compared to two doses only during the Omicron dominant period from December 15, 2021 to January 15, 2022. Breakthrough Omicron infections after 3D + 14 days occurred in 1,315 HCWs. Omicron infections were mild, with 16% of 3D and 11% 2D HCWs being asymptomatic. DISCUSSION: Study demonstrates improved vaccine-derived protection against COVID-19 infection in 3D versus 2D mRNA vaccinees during the Omicron surge. The advantage of 3D vaccination was maintained irrespective of prior COVID-19 infection status.

INTRODUCTION

The Omicron variant (B.1.1.529 and associated lineages B.1., B1.1, B.2 and B.3) can evade vaccine and natural immunity due in part to several mutations in the spike protein region [[1], [2], [3], [4], [5]]. First identified in November 2021 in Botswana and South Africa, Omicron was designated a variant of concern by the World Health Organization (WHO) within a month after its emergence [6]. The US identified its first Omicron case on December 1, 2021 and the Northeast region including New York State witnessed the earliest and steep rise in case numbers, including among vaccinated individuals.

Prior to Omicron we previously reported on the effectiveness of COVID-19 mRNA vaccines BNT162b2 (BioNTech and Pfizer) and mRNA-1273 (Moderna) in a cohort of NYC HCWs during the Alpha and Delta surges. Our results demonstrated high clinical effectiveness of the mRNA vaccines, with minimal waning of protection against mild-moderate Delta infection [7]. The observed higher transmissibility of Omicron variant compared to Delta among vaccinated individuals requires a re-evaluation of the effectiveness of 2-dose (2D) and 3-dose (3D) mRNA vaccines among US HCWs. This study compares SARS Cov-2 infection rates among 2D and 3D mRNA vaccinated NYC healthcare workers during the Omicron surge in December 2021- January 2022. We also describe the clinical characteristics of cases and assess the effect of prior COVID infection on vaccine effectiveness.

METHODS

Memorial Sloan Kettering Cancer Center (MSKCC), a 514-bed tertiary cancer center in New York City that employs over 21,000 individuals. A COVID vaccine mandate (for 2D primary series) went into effect for New York State HCWs on September 21, 2021. CDC recommended 3D for US HCW on September 24, 2021 and MSKCC made them available on September 27th, 2021 (Supplementary Figure 1).

HCW testing policy: In response to the Omicron surge HCW testing was prioritized for symptomatic employees. Testing in the community was encouraged for asymptomatic HCWs with non-workplace related exposures. Workplace exposures were limited due to universal masking. All positive results regardless of testing method required reporting to MSKCC Employee Health and Wellness Service (EHWS) through an automated survey. Clinical characteristics of HCW infections were obtained from a dedicated EHWS database deployed for symptom self-reporting through an electronic questionnaire during the Omicron surge, whereas they were previously collected during clinician interviews for contact tracing and return-to-work clearance.

Laboratory Methods

SARS-CoV-2 RNA test

For HCWs tested at MSKCC, COVID-19 diagnosis was made through detection of viral RNA in nasopharyngeal swabs (NPS) or saliva samples using two real-time reverse transcriptase PCR (RT-PCR) tests: the TaqPath™ COVID-19 Combo Kit (Thermo Fisher Scientific, Waltham, MA) or the Cobas® SARS-CoV-2 test (Roche Molecular Diagnostics, Indianapolis, IN). Performance of these RT-PCR on saliva samples was previously described [8, 9]. Samples were reported as positive per manufacturers’ instructions.

Statistical Analysis

To evaluate the impact of three mRNA doses on protection against Omicron variant, we compared estimates of test positivity rates among 3D + ≥ 14 days and 2D + ≥ 14 days vaccinated HCWs during the NYC Omicron surge from 12/15/21- 1/15/22 (Supplementary Figure 3). To estimate incidence rates in these groups, a rolling risk set was defined each day consisting of all currently employed HCWs on that day. If HCWs ended their employment at MSKCC they were removed from the rolling cohort due to incomplete access to vaccination and testing records. Newly hired employees entered the cohort at date of hire, as vaccination records were known but testing information was not usually available prior to their employment. Temporary contingent employees were excluded in rate estimates due to incomplete records. Other HCW exclusion criteria are outlined in Supplementary Figure 2. Using this rolling cohort, we estimated the rate ratio of total number of positive tests in each vaccination group over the number of person-days in each vaccination category. 95% confidence intervals (CIs) were estimated for rate ratios using 1000 bootstrap iterations and the percentile method to approximate confidence bounds. “Effectiveness” (percent relative effect) was calculated as 1 minus the rate ratio (RR).

To adjust for changing background community infection rates and visualize potential variations in vaccine effectiveness over the course of omicron period, daily and weekly (daily estimates X 7) incidence rates were calculated by dividing the total number of positive tests each day by the number of HCWs in each vaccination category each day. Rates were smoothed using a 7-day moving window.

For analysis of potential effect of prior COVID-19 positives on vaccine effectiveness, a subset of employees who were employed since 11/1/2020 were used, including individuals with prior infection with any variant. Among this subset, vaccination categories were further broken down into the following groups: 1) 3D + ≥ 14 days without prior infection, 2) 3D + ≥ 14 days with prior infection 3) 2D + ≥ 14 days without prior infection 4) 2D + ≥ 14 days with prior infection. Rate ratios were calculated between these groups as described above.

For all analyses, any HCWs with positives tests within 90 days of each other were presumed to be part of the same infection, except for 2 HCWs who had infections on either side of the transition date from Delta to Omicron dominance in NYC who reported distinct clinical syndromes. 3D Vaccine breakthrough (BT) infections were defined as detection of SARS-COV-2 RNA in a respiratory or saliva specimen or a positive antigen test in a nasal swab (performed on or after December 1, 2021) collected from a HCW ≥14 days after receipt of 3D mRNA vaccine, and > 28 days from completion of primary two-dose vaccine series. All analyses were conducted in R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria).

The MSKCC Institutional Review Board granted a HIPAA approval to conduct the study.

RESULTS

Rate Ratio Calculations

Of the 21, 557 HCWs employed at MSKCC as of 12/15/2021 and eligible for inclusion, 20,857 are included in the evaluable cohort for incidence rate ratio calculations. As of study end date (1/15/2022) 20, 864 HCWs were employed at the study institution. Of these, 20,700 (99.2%) had record at least 1 dose of a COVID vaccine, 20,660 (99.0%) had recorded 2 doses, and 12,461 (59.7%) had a record of three doses. 1% of HCWs in the cohort had a medical exemption from the vaccine mandate or were newly hired and completing their initial vaccine series. Among 2D recipients employed at study end, the median time from administration of second dose to study end was 11.2 months days (IQR 8.9 – 11.6 months). Among 3D recipients, median time from administration of third dose to study end was 67 days (IQR 38 – 87 days). HCWs who received a third dose were more likely to have at least one COVID test on record compared to those who did not (79% vs 70%, p < 0.001) (Supplementary Figure 4).

Infections after 2D and 3D

Laboratory-confirmed SARS CoV-2 infections occurred in 3203 vaccinated individuals during the Omicron dominant period (December 15, 2021 – January 15, 2022), including 1,315 infections in HCWs who had received 3D + ≥ 14 days and 1,888 who received 2D + ≥ 14 days. In contrast, there were 509 infections in vaccinated individuals during the Delta dominant period (July 1, 2021-December 14th, 2021), 36 of which occurred in HCWs with 3D + ≥ 14 days and 473 of which occurred in HCW 2D. + ≥ 14 days.

Overall, there were 1,351 3D BT cases across both the Delta and Omicron dominant periods. Among all these 3D BT cases the median time between booster shot and positive SARS-CoV-2 test was 62 days (IQR 44 days – 78 days).

Figure 1 depicts weekly rate ratios for infections in 3D + ≥ 14 days vs 2D + ≥ 14 days recipients across the period of booster availability at the study institution. The overall rate ratio comparing 2D protection to 3D protection was 0.667 (95% CI, 0.623, 0.713).

Figure 1

Weekly Rate Ratios for infections in 3D vs 2D HCW Recipients 203x177mm (300 x 300 DPI).

The comparative vaccine effectiveness of 3D vs 2D for lab confirmed SARS CoV-2 infection for the Omicron dominant period (After Dec 15,2021) was 33.2% (95% CI, 28.7%, 37.7%)

Impact of prior COVID infection on BT infections

Of all 3D BT infections during Delta and Omicron periods, 7.2% (98/1,351) had a record of a prior COVID infection. Of 1,315 3D breakthrough infections during the Omicron period, 94 (7.1%) had a previous COVID infection. In contrast, for 1,888 2D BTs during omicron period, 2 09 (11.1%) had a prior COVID infection. 18,152 of the 21,557 HCWs employed at the start of omicron had been employees since at least 11/1/2020 and therefore had adequate COVID testing records to examine effects of prior positives on rate ratios. In this subset, 7.9% (93/1172) of 2D BTs had a recorded prior positive and 13.1% (205/1570) of 2D BTs had a prior positive.

Rate ratios comparing incidence rates among those with a prior documented positive test of any variant with those with no prior infection were calculated between each vaccine group (Figure 2 ). Within the 2D and 3D groups, rate ratios calculated from 12/15/2021 to 1/15/2022 comparing those who had an infection prior to their Omicron infection vs those who did not were less than 1, indicating an additional protective effect of a prior infection (2D Prior + vs. 2D No Prior +: 0.635 [0.545, 0.733], 3D Prior + vs. 3D No Prior +: 0.768 [0.622, 0.926], Supplementary Table 1). For patients with prior infection, protection against Omicron was better with 3 doses than 2 doses (3D +prior infection vs 2D + prior infection 0.757 [0.587, 0.935], highlighting the added benefit of additional vaccine dose to protection derived from prior infection.

Figure 2

Rate Ratios Comparing Positivity Rates by Vaccine Status and Prior Documented Infection.269x213mm (300 x 300 DPI).

Clinical and Demographic Characteristics of HCWs w 3D infections

Eighty percent (n= 1061) of HCWs with 3D breakthrough infections with Omicron had completed the symptom survey. Respondents median age was 34 years (range 20-78 years). Sore throat (63%) and cough (54%) were the predominant symptoms. Omicron infections were mild, with 16% of 3D and 11% 2DHCWs being asymptomatic. No hospitalizations were noted in 3D recipients compared to 1 reported among 2D recipients (Supplementary Table 2). No COVID-related deaths were reported in either group during the Omicron surge.

DISCUSSION

Our study from an established cohort of over 20,000 NYC HCW shows a benefit of 3D vs. 2D of mRNA vaccine against infection caused by the Omicron variant. The comparative VE of 3D vs. 2D against illness was 32.8%. No hospitalizations or severe infections were reported among 3D vaccinees. Further, our data suggests that HCWs with prior COVID-19, booster doses may provide additional protection against Omicron infection.

The sudden unexpected emergence of the Omicron variant challenged US healthcare systems because of the sheer scale of spread in patients and HCWs. The higher transmissibility of the variant fueled this among vaccinated and previously infected individuals due to its immune evasion properties and concerns about waning immunity of the primary 2D vaccine series [2, 5, 10]. The life-saving impact of booster vaccination against the dynamic COVID-19 landscape cannot be underestimated [11]. Understanding the vaccine effectiveness and subsequent impact of Omicron in a highly vaccinated healthcare workforce may elucidate how healthcare systems can preemptively manage future surges, devise effective vaccination policies, and combat vaccine hesitancy.

Third doses for HCW were approved in the US with some delay compared to other countries. A systematic assessment of booster vaccine effectiveness among US HCW is limited, especially against Omicron, despite growing evidence of the benefits of three mRNA vaccine doses in other populations. Data from Israel, where waning protection against illness and severe disease prompted booster administration in July 2021, demonstrated restored protection across all age groups [12, 13]. Further, preliminary studies support higher vaccine effectiveness of booster doses for HCWs among nearly 2000 HCWs at a single medical center in Israel [3D vs. 2D recipients infection rates at 39 days following booster, 12.8 vs. 116 per 100,000 person-days] [14, 15].

Consistent with reports on immune evasiveness of Omicron, recent data from the United Kingdom's PHE shows that the vaccine effectiveness against symptomatic Omicron infection was much lower than against the Delta variant in boosted individuals[16]. Protection against hospitalization was sustained: 75%-90% VE for Pfizer 3D recipients and > 90% with Moderna with 8-9 week follow up. Similarly, reports from the US show slightly lower vaccine effectiveness of the booster dose against emergency department visits and hospitalization for Omicron compared to Delta [15]. Our other important finding demonstrates slightly improved clinical protection against Omicron with the third dose among HCW with prior COVID-19 infection compared to those with two doses only. Although studies should confirm these findings in other populations, the observations are consistent with emerging evidence on the benefit of vaccination even in those with pre-Omicron infection. For example, in a review of registry data from California and New York through November 2021, case rates for infection were substantially lower among vaccinated persons with a prior COVID-19[17]. Previous COVID-19 infection is one of the reasons for booster hesitancy. Although vaccination safety in those with prior infection is well established, we provide early evidence that suggests better clinical protection against Omicron in 3D vaccinated persons with prior infection.

Evaluating vaccine effectiveness during a novel variant surge is subject to several limitations. Availability of PCR testing was adjusted to prioritize symptomatic testing which may have led to an underestimate of asymptomatic Omicron infections across both 2D and 3D HCWs, despite accessibility of home testing. Additionally, symptom assessment was conducted only at disease onset and via optional self-reported survey, which may have led to increased symptom reporting in those with health-seeking behavior. Boosted individuals sought testing, and tested more often reflecting a potential bias towards healthcare-seeking behavior in the 3D group, and which may have resulted in under-surveillance of infections in the 2D group. Although 3D HCW had more tests overall, 2D HCW testing rates disproportionately increased during the last two weeks of 2021 and first week of 2022 corresponding to many holidays (Supplementary Figure 4). This increase in testing surveillance occurred concurrently with an increase in incidence rates in the 2D group and a decrease in rate ratios when comparing 2D to 3D HCWs in those same weeks and thus, more accurately reflect VE of 3D in our cohort.

Additionally, estimates of positive test incidence rates may be confounded by age or job type. A sensitivity analysis estimating stratum-specific rate ratios showed comparable estimates of effectiveness among these strata and compared with the overall estimates presented in the paper (<5% difference, Supplementary Table 3).

We also interrogated the possibility of inflated 2D protection from 3D -14 day recipients in a sensitivity analysis removing these individuals which showed rate ratios comparable to the ones presented in the main study (0.631 95% C: 0.591, 0.671).

Delta and Omicron cocirculated in NYC very briefly, which may have led to inconsequential variant mis-categorization in early December.

In summary, our study confirms that HCWs vaccinated with three doses have better protection against Omicron infection than those immunized with only two doses. Further, vaccination enhances clinical protection in those with prior COVID-19 infection. Therefore, US jurisdictions should adopt HCW booster mandate programs more broadly to optimize protection against emerging variants.

Conflict of Interest

E.R, K.W., A.L, C.P., K.J., T.M., D.K., V.S., M.K. declare no conflicts of interest. S.F. has received payment or honoraria from Amgen, GSK, Daiichi, Astra Zeneca, G1, Coherus, Regeneron outside the scope of this work. N.E.B. reports grants from GenMark Dx, personal fees from Roche Diagnostics, outside the submitted work.

Funding

Supported by the Memorial Sloan Kettering Cancer Center core grant (P30 CA008748), the Jack and Dorothy Byrne Family Fund (NEB, MK), Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine.

Author Contributions

MK conceptualized this project. EVR, KW, AL, CP performed data curation. KW and VS completed formal analysis. KJ, TM, NEB conducted sequencing as part of investigation to assign variant lineages. EVR wrote the original draft and all authors provided critical review and commentary on all drafts.