Effectiveness of two coronavirus disease 2019 (COVID-19) vaccines (viral vector and inactivated viral vaccine) against severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection in a cohort of healthcare workers

Objective: We investigated real-world vaccine effectiveness for Oxford-AstraZeneca (ChAdOx1) and CoronaVac against laboratory-confirmed severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection among healthcare workers (HCWs). Methods: We conducted a retrospective cohort study among HCWs (aged ≥18 years) working in a private healthcare system in Brazil between January 1, 2021 and August 3, 2021, to assess vaccine effectiveness. We calculated vaccine effectiveness as 1 − rate ratio (RR), with RR determined by adjusting Poisson models with the occurrence of SARS-CoV-2 infection as the outcome and the vaccination status as the main variable. We used the logarithmic link function and simple models adjusting for sex, age, and job types. Results: In total, 13,813 HCWs met the inclusion criteria for this analysis. Among them, 6,385 (46.2%) received the CoronaVac vaccine, 5,916 (42.8%) received the ChAdOx1 vaccine, and 1,512 (11.0%) were not vaccinated. Overall, COVID-19 occurred in 6% of unvaccinated HCWs, 3% of HCWs who received 2 doses of CoronaVac vaccine, and 0.7% of HCWs who received 2 doses of ChAdOx1 vaccine (P < .001). In the adjusted analyses, the estimated vaccine effectiveness rates were 51.3% for CoronaVac, and 88.1% for ChAdOx1 vaccine. Both vaccines reduced the number of hospitalizations, the length of hospital stay, and the need for mechanical ventilation. In addition, 19 SARS-CoV-2 samples from 19 HCWs were screened for mutations of interest. Of 19 samples, 18 were the γ (gamma) variant. Conclusions: Although both COVID-19 vaccines (viral vector and inactivated virus) can significantly prevent COVID-19 among HCWs, CoronaVac was much less effective. The COVID-19 vaccines were also effective against the dominant γ variant.

protective equipment (PPE) have a 23% higher risk. 1,2 In addition, when compared to HCWs reporting adequate access to PPE and who were not caring for patients with COVID-19, HCWs caring for patients with documented COVID-19 had a nearly 5-times higher risk of testing positive if they had adequate access to PPE and a nearly 6-times higher risk if they had inadequate access to PPE. 2 These reports emphasize the need for effective vaccines, especially among frontline HCWs.
Over the last few months, multiple studies have yielded a large amount of data from different institutions that provided real-world data on short-term vaccine effectiveness. 3,4 The great majority of these studies examined COVID-19 mRNA vaccines that significantly prevented symptomatic and asymptomatic severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection among HCWs. 5 However, data regarding the vaccine effectiveness of other COVID-19 vaccines (eg, viral vector or inactivated virus) are limited.

Population and setting
This retrospective cohort study was conducted between January 1, 2021, and August 3, 2021, in Brazil. We included all adult HCWs (aged ≥18 years) working at the Hospital Israelita Albert Einstein (HIAE). The HIAE is a Brazilian, nonprofit, healthcare, education, and research organization, with its headquarters in the city of São Paulo. HIAE manages a diverse healthcare system, including primary healthcare to tertiary-care services, in the public and private healthcare sectors. This hospital operates 40 healthcare units, mainly in the state of São Paulo, and in 2020 it had ∼700,000 emergency department visits, 900,000 outpatient visits, and 70,000 hospital discharges overall. Since the beginning of the COVID-19 pandemic, HCWs with COVID-19 symptoms had access to free-of-charge SARS-CoV-2 RT-PCR testing conducted by the institution's laboratory. Vaccination with 2 doses of CoronaVac vaccine, 21 days apart, and with 2 doses of the ChAdOx1 vaccine, 12 weeks apart, were evaluated for COVID-19 vaccine effectiveness. HCWs were considered unvaccinated if no COVID-19 vaccine doses were received. Individuals who tested positive for SARS-COV-2 prior to the first vaccine dose, between vaccine doses, or before 14 days after the second vaccine dose, and individuals who had been vaccinated before the study period, were excluded from the study. We also excluded HCWs who received the Pfizer COVID-19 vaccine because the sample size (∼130 HCWs) was too small to obtain an estimate of vaccine effectiveness (Supplementary Appendix 1 online).

Next-generation sequencing of viral full-length genome
We extracted total nucleic acid from the naso-oropharyngeal (NOP) swab samples with QIAamp Viral RNA Mini kit (QIAGEN, Hilden, Germany). After purification and concentration, DNAse I treatment, and depletion of human ribosomal RNA, the samples were subjected to random amplification. 6 The preparation of sequencing libraries for the Illumina platform was carried out with DNA Prep (Illumina, San Diego, CA) using the random 2-step PCR amplification product as input. The libraries were quantified with the Qubit instrument (Thermo Fisher Scientific, Waltham, MA) and were loaded on the NextSeq 550 equipment (Illumina) for sequencing with MID 300 paired-end reads (Illumina).

Outcome measures and statistical analyses
Laboratory-confirmed COVID-19 was considered the primary outcome to calculate vaccination effectiveness after 2 doses of a COVID-19 vaccine (CoronaVac or ChAdOx1). RT-PCR testing for the diagnosis of COVID-19 was performed only on symptomatic HCWs. Hospitalization related to COVID-19, length of stay, ICU admission, necessity of mechanical ventilation and death were secondary outcomes. Vaccination status and SARS-CoV-2 RT-PCR results of all study participants were obtained from institutional electronic records. We excluded those with a positive COVID-19 diagnosis before January 15, 2021, because it corresponded to data from the first vaccine (January 1, 2021) plus 14 days. For those vaccinated, the initial follow-up date was 14 days after the second vaccine dose. The last date was defined as the date COVID-19 was diagnosed, or up to August 3, 2021, for the censored cases without a positive diagnosis of COVID-19.
The qualitative variables were characterized using absolute and relative frequencies in general and by interest groups; for comparisons, we used the χ 2 or the Fisher exact test. The quantitative variables have been reported as medians, interquartile range (IQR, first and third quartiles), minimum and maximum values due to the asymmetry observed in the variables, 7 and comparisons were performed via nonparametric Kruskal-Wallis tests. Vaccine effectiveness was calculated as 1 − rate ratio (RR), 8 with RR obtained by adjusting Poisson models with SARS-CoV-2 infection confirmed by RT-PCR as the outcome and vaccination status as the main exploratory variable, in addition to 95% confidence intervals. We used the logarithmic link function to estimate unadjusted models and models adjusted for sex, age, and HCW job type (ie, direct patient contact vs no direct patient contact). The cumulative incidence curves of COVID-19 for the vaccinated and unvaccinated groups were estimated using the Kaplan-Meier method 9 and the cumulative incidence estimated at 30 and 90 days with unadjusted models. All analyses were performed with the R software environment for statistical computing and graphics version 4.1.0. 10 All reported tests were 2-sided, and P < .05 was considered significant. The study was approved by the Hospital Israelita Albert Einstein Ethics Committee (no. CAAE 47110421.7.0000.0071), which waived the need for informed consent.
During the study period, 325 HCWs (2.4%) were diagnosed with COVID-19. For the unvaccinated HCWs, the cumulative incidences of COVID-19 were 0.73% at 30 days of follow-up and 3.57% at 90 days of follow-up. The cumulative incidences were 0.85% at 30 days and 2.32% at 90 days for those vaccinated with the CoronaVac vaccine. The cumulative incidences were 0.58% in 30 days and 0.73% in 90 days for those vaccinated with the ChAdOx1 vaccine ( Fig. 1). None of the HCWs (vaccinated or unvaccinated) died during the study period.

Discussion
This retrospective study revealed that the estimated vaccination effectiveness among HCWs against symptomatic COVID-19 were 51.3% for CoronaVac and 88.1% for AstraZeneca after adjusting for age, sex, and job type. Both a viral vector vaccine (ChAdOx1) and an inactivated viral vaccine (CoronaVac) reduced the number of COVID-19 cases, the number of hospitalizations, the length of hospital stay, and the need for mechanical ventilation. These vaccines were even effective against a new variant of concern in Brazil, the γ (gamma) variant.
Based on a recent published systematic literature review evaluating short-term vaccination effectiveness between December 2020 and April 2021, COVID-19 vaccines (primarily the mRNA vaccines) decrease symptomatic COVID-19 infection with vaccine effectiveness of 92.8%. 5 Our study showed that the estimated vaccine effectiveness rates after 2 doses of CoronaVac and ChAdOx1 among HCWs were lower than the vaccine effectiveness rates of mRNA COVID-19 vaccines among the general population reported in the randomized trials 11,12 and also in a noncontrolled setting. 3 A randomized clinical trial evaluating vaccine effectiveness of CoronaVac among HCWs in Brazil reported vaccine effectiveness after 2 doses of 50.7%. 13 Another randomized clinical trial of CoronaVac in Turkey reported an estimated vaccine effectiveness after 2 doses of 83.5%. 14 Both clinical trials were conducted in 2020, prior to the emergence of the variants of concern. More recent observational studies evaluating the vaccine effectiveness of the CoronaVac vaccine did not include genomic surveillance for SARS-CoV-2 virus but reported the circulation of at least 2 viral lineages considered to be variants of concern: B.1.1.7 (α variant) 15 and P.1 (γ variant). 15,16 Results from these studies after 2 doses, in a prospective national cohort study from Chile, demonstrated that the estimated vaccine effectiveness of CoronaVac in a general population was 65.9%. 15 Results from a test-negative case-control study of the vaccine effectiveness of CoronaVac vaccine among HCWs in Manaus, Brazil, where the γ variant was also predominant, showed that the estimated vaccine effectiveness after 2 doses was low (36.8%) against COVID-19. 16 In terms of the ChAdOx1 vaccine, a randomized clinical trial conducted in Brazil, South Africa, and the United Kingdom showed that the vaccine effectiveness of ChAdOx1 after 2 doses was 62% against COVID-19. 17 Results from a test-negative case-control study evaluating the vaccination effectiveness of ChAdOx1 vaccine after 2 doses for the B.1.1.7 (α variant) and the δ (delta) variant were 74.5% and 67.5%, respectively. 18 Although it is not clear why the vaccine effectiveness rates in our present study were higher compared to vaccine effectiveness rates in previously published studies. 17,18 Possible explanations are the strict infection control policies in our institution and adequate PPE throughout the pandemic while many other institutions suffered critical shortages of PPE. 1,2 Although a peak of COVID-19 was observed in March-June 2021, the community incidence of COVID-19 was relatively stable and the γ (gamma) variant was dominant during the study period.
ChAdOx1 (Oxford-AstraZeneca) and CoronaVac were the first COVID-19 vaccines authorized by the Brazilian Heath Surveillance Agency, 19 and HCWs were considered the priority group to receive them as of January 2021. 20 We observed that HCWs who received 2 doses of CoronaVac were more likely to provide direct patient care in comparison to HCWs that received 2 doses of the ChAdOx1 vaccine. This difference can be explained by the CoronaVac vaccine being the first available COVID-19 vaccine in our institution, and for that reason, the frontline HCWs were prioritized to receive the COVID-19 vaccine. Later in the pandemic, our institution started using ChAdOx1 vaccine, which was mainly given to nonclinical persons. The duration of our study (8 months) among HCWs is justified, particularly to understand the short-term vaccination effectiveness in the context of a global pandemic with a novel pathogen. 21 We collected data during a rapid vaccination campaign during a period with one of the highest community transmission rates of the pandemic, which allowed for a relatively short follow-up period and the estimation of the prevention of COVID-19 cases, related hospitalization, necessity of mechanical ventilation, and ICU stay. Both CoronaVac and ChAdOx1 vaccines were effective at preventing COVID-19 and serious illness (hospitalizations, necessity of mechanical ventilation and ICU care).
During the HCW COVID-19 vaccine campaign, the dominant variant in circulation was P.1 (γ variant), and both COVID-19 vaccines (CoronaVac and ChAdOx1) showed effectiveness against this variant. More studies are needed regarding the SARS-CoV-2 variants of concerns (VOC) that have multiple spike-protein mutations and appear to be more infectious or cause more disease than other circulating SARS-CoV-2 variants. 22 Some deletions in the spike-protein mutations can alter the shape of the spike and may help it evade some antibodies. 23 No COVID-19 vaccine is 100% effective against SARS-CoV-2 infection, consistent with COVID-19 breakthrough infections reported in HCWs after COVID-19 vaccination. 24,25 We detected a clear effect of the vaccines against the new variants (mainly P.1).  Our study had several limitations. First, this was an observational study, subject to multiple biases 26 ; however, this is the most common study design in the infection prevention literature. 26 Second, we estimated vaccine effectiveness based on short-term duration, and longer-term observational studies are needed to assess sustained immune response and vaccine effectiveness. Third, due to the uncertainty related to the number of days required to develop immunity postvaccination, we decided to adopt the CDC definition for the CoronaVac vaccine and for the ChAdOx1 vaccine, which defines people fully vaccinated as being ≥14 days after the second dose in a 2-dose series (Pfizer/BioNTech or Moderna), or ≥14 days after a single-dose vaccine (Johnson & Johnson/Janssen). 27 Other studies adopted different definitions of a fully vaccinated person. 5 Currently, no postvaccination time limit on fully vaccinated status has been established. In addition, the CDC defines unvaccinated people as individuals of all ages including children who have not completed a vaccination series or have not received a single-dose vaccine. 27 Fourth, we have not reported nonneutralizing viral antigen-binding antibody levels in our HCW cohort study. However, the US Food and Drug Administration (FDA) does not recommend antibody testing for SARS-CoV-2 to determine