key: cord-0743909-dnb3uxm7 authors: Kislaya, I.; PERALTA SANTOS, A.; Borges, V.; Vieira, L.; Sousa, C.; Ferreira, B.; Pelerito, A.; Gomes, J. P.; Pinto Leite, P.; Nunes, B. title: Comparative complete scheme and booster effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infections with SARS-CoV-2 Omicron (BA.1) and Delta (B.1.617.2) variants date: 2022-02-02 journal: nan DOI: 10.1101/2022.01.31.22270200 sha: f85dd5c9feb682d0f48b8985a66e260bd23769b1 doc_id: 743909 cord_uid: dnb3uxm7 Introduction Information on vaccine effectiveness and viral loads in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sub-lineages) VOC according to vaccination exposure (primary or booster) and time since primary vaccination and to compare cycle threshold (Ct) values between Omicron and Delta VOC infections according to the vaccination status as an indirect measure of viral load. Methods We developed a case-case study using data on RT-PCR SARS-CoV-2 positive cases notified in Portugal during weeks 49-51 2021. The odds of vaccination in Omicron cases were compared to Delta using logistic regression adjusted for age group, sex, region and week of diagnosis and laboratory of origin. RT-PCR Ct values were compared by vaccination status and variant using linear regression model. Results Higher odds of vaccination were observed in cases infected by Omicron (BA.1) VOC compared to Delta (B.1.617.2) VOC cases for both complete primary vaccination (OR=2.1; CI 95% :1.8 to 2.4) and booster dose (OR= 5.2; CI 95%: 3.1 to 8.8), indicating vaccine effectiveness reduction against Omicron. No differences in distribution of Ct-values between these two VOC were observed for any vaccination exposure categories. Conclusion Consistent lower VE was observed against Omicron infection. Complete primary vaccination may not be protective against SARS-CoV-2 infection in regions where Omicron variant is dominant, but a massive rollout of booster vaccination campaign can contribute to reduce SARS-CoV-2 incidence in the population. Information on vaccine effectiveness and viral loads in a context of novel variants of concern (VOC) emergence is of key importance to inform public health policies. This study aimed to estimate a measure of comparative vaccine effectiveness between Omicron (BA.1) and Delta (B.1.617.2 and sublineages) VOC according to vaccination exposure (primary or booster) and time since primary vaccination and to compare cycle threshold (Ct) values between Omicron and Delta VOC infections according to the vaccination status as an indirect measure of viral load. We developed a case-case study using data on RT-PCR SARS-CoV-2 positive cases notified in Portugal during weeks 49-51 2021. The odds of vaccination in Omicron cases were compared to Delta using logistic regression adjusted for age group, sex, region and week of diagnosis and laboratory of origin. RT-PCR Ct values were compared by vaccination status and variant using linear regression model. Higher odds of vaccination were observed in cases infected by Omicron (BA.1) VOC compared to Delta (1) has been classified by the World Health Organization(2) as a variant of concern (VOC), as it presents several mutations associated with increased transmissibility, immune escape, and higher risk of reinfection (3, 4) . The Omicron (BA.1) variant yields an S gene target failure (SGTF) signal (due to the deletion Δ69-70 in the Spike protein) in some PCR tests (e.g. TaqPath COVID-19, ThermoFisher, Waltham, MA, United States), which can be used as a proxy for Omicron detection and differentiation from the circulating Delta (B.1.617.2 and sub-lineages) variant (in which the Δ69-70 is rarely detected)(5). The Omicron had a swift rise in Europe becoming dominant in a few weeks in England, Scotland and Denmark (6) , and the European Center for Disease Prevention and Control (ECDC) risk assessment (7) referred that would become dominant in early January 2022 in all European Union member states. Considering COVID-19 vaccination, most European countries have ongoing mass population vaccination, with considerably high vaccine coverage in some countries. Hence, it is fundamental to understand how this novel VOC impacts the transmission dynamics in highly vaccinated populations. The first studies on neutralization assays revealed an extensive but incomplete escape of Cominarty BNT162b2 elicited neutralization (8) , but booster dose increased the neutralization (9) . These preliminary in-vitro results were confirmed by the first vaccine effectiveness studies in England and Scotland (10, 11) for symptomatic infections and hospitalizations for both complete vaccination schemes and booster doses. UK study estimated a reduction of vaccine effectiveness (VE) for symptomatic infection with the Omicron with no effect for two ChAdOx1 (Vaxzevria) doses and 34% and 37% from 15 weeks post dose 2 of BNT162b2 (Cominarty) (10) . Another study in Denmark found similar results with reduced VE for Omicron infection compared with Delta for two doses of BNT162b2 (Cominarty) and mRNA-1273 (Spikevax), with an increase in VE after a booster dose (12) is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint To estimate a measure of comparative COVID-19 vaccine effectiveness of complete primary vaccination scheme and of the booster dose against the SARS-CoV-2 Omicron (BA.1) versus Delta (B.1.617.2 and sub-lineages) VOC we used a case-case study design (14) . Similar approach was used and has been previously described elsewhere (13) . This design has been proven useful to address question about COVID-19 vaccine effectiveness in a context of novel VOC emergence comparing directly the odds of vaccination between RT-PCR-positive cases infected with different VOC. Considering cases of the Omicron SARS-CoV-2 infection as cases of interest, and Delta infections as the reference group, higher vaccination odds in Omicron cases in a case-case study are indicative of a lower effectiveness of COVID-19 vaccines against the Omicron comparative to the Delta VOC. For the second objective, we have used TaqPath Ct values for nucleocapsid (N) and open reading frame 1ab (ORF1ab) gene as a proxy to compare viral loads for Omicron and Delta cases by vaccination status (15) . Ct values indicate a number of RT-PCR cycles required for amplification of SARS-CoV-2 RNA and have been used to infer infectiousness and transmissibility on others VOC (16 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint or more years old since younger age groups were not yet eligible for the booster vaccination at the time of the study and to those without history of previous SARS-CoV-2 infection (19) . Individuals with missing data on National Health Service User number, age, sex, place of residence or diagnosis date were excluded from all analyses. We linked laboratory data on Ct values and whole-genome sequencing on SARS-CoV-2 positive cases collected by the National SARS-CoV-2 Genomic Surveillance Network and three private molecular SARS-CoV-2 variants were classified by viral whole-genome sequencing (WGS) or inferred for nonsequenced samples based on data on S-gene amplification using the TaqPath™ Covid 19 CE IVD RT-PCR Kit (Thermo Scientific™) assay, as follows: no S-gene amplification (Omicron BA.1) and S-gene amplification (Delta). TaqPath S-positive samples could be confidently classified as Delta, since this VOC was dominant in Portugal since the last Summer (weekly frequencies above 99% between weeks 30 and 47, when Omicron started emerging)(https://insaflu.insa.pt/covid19/). In Portugal four vaccines are authorized for primary vaccination (Cominarty, Spikevax, Vaxzevria with 2-dose scheme and Janssen COVID-19 with a single dose scheme) and mRNA vaccines (Cominarty and Spikevax) are used for the boost (19) . is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. To avoid small sample size bias, we will not present estimates for vaccine exposure categories with sample size n<20. This study complied with legal and ethical requirements for research on genomic epidemiology of novel coronavirus (SARS-COV-2). Characteristics of participants infected with Omicron and Delta VOC were compared using the chisquare test. Logistic regression adjusted for age group, sex, region of residence, week of diagnosis and laboratory of origin was used to estimate confounding-adjusted odds of complete/boosted vaccination in Omicron cases compared to Delta SARS-CoV-2 cases. An odds ratio (OR) equal to one (OR=1) indicates no difference in odds of vaccination between Omicron and Delta cases and, thus, a proxy of no difference between vaccine effectiveness against Omicron versus Delta VOC. An odds ratio higher than one (OR>1) indicates a higher odds of vaccination among Omicron cases, as such, lower . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint vaccine effectiveness against Omicron compared to Delta VOC. Otherwise an odds ratio lower than one (OR<1) indicates a lower odds of vaccination among Omicron cases, and a higher vaccine effectiveness against Omicron in comparison with Delta VOC. We also provide estimates of vaccine effectiveness against the Omicron for complete primary vaccination scheme and for the booster dose by combining previously published vaccine effectiveness estimates against Delta and OR estimated in this study using the following formula: To assess the bias of misclassification error associated with the SGTF method, we included only cases identified exclusively through WGS. To address if having been infected and vaccinated was associated with lower infectiousness in any of the studied VOCs, we also restricted analysis to the samples with is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Of a total of 15,001 sample collected during the study period for population aged 12 or more years old, 13 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint Due to small sample size of cases classified by WGS and absence of cases with previous infection among those with booster dose, it was not possible to perform any other sensitivity analysis for population aged 50 or more years old. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Figure S1 ). Differences in mean Ct-values between Omicron and Delta cases were also not significant for all vaccination exposure levels (unvaccinated, primary partial vaccination, complete primary vaccination). Considering time since complete primary vaccination, we observed differences between Delta and Omicron cases only for cases with less than 113 days since complete primary vaccination (MD=-0.7; CI 95%: -1.13; -0.28), indicating slightly lower Ct (higher viral loads) in Omicron cases. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint For cases with 50 or more years of age, no statistically significant differences in mean Ct values by VOC or vaccination status were observed, distribution of Ct is shown in supplementary material ( Figure S2 ). 0.32(-0.08 to 0.73) * Obtained by linear regression model with adjustment for age, sex, region, week of diagnosis, laboratory of origin. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint between Omicron and Delta regardless time since vaccination was similar to primary VE reduction against Omicron VOC observed in UK study (10) . Translation of case-case OR estimates to vaccine effectiveness estimates against Omicron VOC infection resulted in substantially lower and even null COVID-19 vaccine effect for complete primary vaccination against Omicron (VE ranged between -7.1% and 28.1%). These results are indicative of low or null protection of complete primary vaccination against SARS-CoV-2 infection also observed in other countries (10) (11) (12) For the booster dose, available at the time of the study for population aged 50 or more years old, we estimated an OR of 5.2 (CI95: 3.1 to 8.8) that also indicated a marked reduction of protection against infection (regardless presence of symptoms) with Omicron compared to Delta. However, since booster has been shown to be highly effective against Delta VOC infection (VE: 94.0 (93.4 to 94.6) ), the translation of case-case OR estimates in vaccine effectiveness estimates against Omicron VOC infection, led to estimates ranging from 64.2 to 68.8%. These results were consistent with previous findings from UK study that reported moderate vaccine effectiveness of the booster dose against symptomatic infections with Omicron up to 10 weeks after the booster uptake (10) . However, the protection induced by booster dose may be of short term, since considerable VE waning, in particular against SARS-CoV-2 infection, has been previous reported in literature for primary vaccination. So further studies are required to monitor booster VE against Omicron infection along time. The distributions of Ct-values in our study were similar between VOC and vaccination status. We observed no statistically significant confounding-adjusted mean differences either by vaccination exposure or VOC. Few studies have previously explored the differences in Ct-values between Omicron and Delta VOC. Existing evidence on viral loads differences between Omicron and Delta were not consistent, with studies from Denmark and Switzerland showing similar Ct-value distributions between Delta and Omicron cases (21, 22) , while in France significantly higher Ct values were observed for cases infected with Omicron (23) . No significant differences in the Ct values between people infected with Omicron and people infected with Delta is thus not surprising and it has been . CC-BY-NC 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint corroborated by other studies (21, 22) . In fact, it is believed that the molecular basis underlying Omicron's higher transmissibility likely relies on its mutational pattern involved in alternate entry mechanisms, increased host-cell binding and immune evasion, rather on higher viral loads spread through aerosolization (24, 25) . Our study has several limitations. First, we were unable to differentiate between symptomatic and asymptomatic infections. Second, our study was based on RT-PCR tests, so rapid antigen test widely used in Portugal for SARS-CoV-2 diagnosis (26) were not covered by our data. Although study included cases samples from National SARS-CoV-2 Genomic Surveillance Network and three major clinical pathology laboratories, we cannot exclude that cases included in our study might not be representative of the overall infections detected in Portugal during week 49-51 2021. Hence, we compared age group, sex and region of study sample and the overall cases notified with infection in the same period. We found no significant differences in the sex and age group distribution between the universe of identified cases through rapid or RT-PCR testing and notified to SINAVE and the study sample. However, the north region tends to be overrepresented in our study sample . Third, incentives for testing had changed during the study period, negative tests regardless vaccination status became required to go to restaurants, hotels and to participate cultural events(27). This change may affect study results. However, selection of cases to the study sample was independent from the VOC type and from vaccination status. Fourth, this study did not collected data on comorbidities, considered relevant confounding variables in vaccines effectiveness research. So, we were not able to adjust for comorbidities in our models, neither estimate proportion of those with comorbidities by vaccination status. This can affect study results since individuals with comorbidities, such as immunosuppressed patients were prioritized for additional vaccination dose in Portugal (19) . Finally, to translate case-case result to VE estimates we used previously published estimates of VE against symptomatic infection with Delta, while our study sample included notified infections regardless their symptoms. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Among study strengths, we should mention its large sample size due to use of surveillance data, wellestablished and high positive predictive value in SGTF method to classy infections as Delta or Omicron variants, and the robustness of results when we changed the sampling strategy in our sensitivity analyses (WSG-only or restriction to Ct<25). Although direct comparisons to other studies are challenging due to differences in methodology, outcome and exposure definitions, vaccination calendar, eligibility for booster, vaccine brand-specific policies, testing patterns and other non-pharmacological interventions in place, our findings corroborate the general trend. More specifically our results support a marked reduction of primary and booster vaccination schemes effectiveness in preventing Omicron infections compared to Delta observed in other countries (10, 12) . Our findings suggest that complete primary vaccination may not be protective against SARS-CoV-2 infection in regions where Omicron variant is dominant. Even with lower booster vaccine effectiveness against Omicron, massive roll out and acceleration of booster vaccination campaign can contribute to reduction of number of susceptible to SARS-CoV-2 infection and its incidence in the population. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint We computed estimates of vaccine effectiveness against the Omicron for complete primary vaccination scheme and for the booster dose by combining previously published vaccine effectiveness estimates against Delta and OR estimated in this study using the following formula: is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted February 2, 2022. ; https://doi.org/10.1101/2022.01.31.22270200 doi: medRxiv preprint Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa World Health Organization. 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