Effectiveness of XBB.1.5 Vaccines and Antiviral Drugs Against Severe Outcomes of Omicron Infection in the USA

In the fall of 2023, the US Food and Drug Administration (FDA) authorised the use of the updated Moderna (Sept 11), Pfizer-BioNTech (Sept 11), and Novavax (Oct 3) COVID-19 vaccines containing a monovalent component of the XBB.1.5 variant "to provide better protection against serious consequences of COVID-19, including hospitalization and death", with neither the FDA nor the companies providing clinical evidence.1US Food and Drug AdministrationFDA takes action on updated mRNA COVID-19 vaccines to better protect against currently circulating variants.https://www.fda.gov/news-events/press-announcements/fda-takes-action-updated-mrna-covid-19-vaccines-better-protect-against-currently-circulatingDate: Sept 11, 2023Date accessed: February 20, 2024Google Scholar, 2US Food and Drug AdministrationFDA authorizes updated novavax COVID-19 vaccine formulated to better protect against currently circulating variants.https://www.fda.gov/news-events/press-announcements/fda-authorizes-updated-novavax-covid-19-vaccine-formulated-better-protect-against-currentlyDate: Oct 3, 2023Date accessed: February 20, 2024Google Scholar The National Institutes of Health Guidelines prefer ritonavir-boosted nirmatrelvir to molnupiravir for outpatient treatment of symptomatic patients with COVID-19 at high risk of progressing to severe disease.3National Institutes of HealthCoronavirus disease 2019 (COVID-19) treatment guidelines.https://www.covid19treatmentguidelines.nih.gov/Date: Dec 20, 2023Date accessed: February 20, 2024Google Scholar In this Correspondence, we report data from a large cohort study on the effectiveness of the three XBB.1.5 vaccines and the two oral antiviral drugs, as well as their interaction, against admission to hospital and death from currently circulating SARS-CoV-2 variants. We included all US residents aged 12 years and older in the Cleveland Clinic Health System who had tested positive for SARS-CoV-2 infection in outpatient settings between Sept 12 and Dec 31, 2023 (appendix p 1). Individuals who were tested usually had influenza-like illness or upper respiratory tract infection symptoms. During this period, the dominant variants changed from EG.5 to HV.1 and JN.1, and the proportion of XBB.1.5 declined from 9% to 4% (appendix p 5). In this cohort, 3315 (12·2%) of 27 194 patients had received the XBB.1.5 vaccines (66% Pfizer-BioNTech, 32% Moderna) before the time of SARS-CoV-2 testing, and 12 387 (45·6%) of 27 194 patients received the oral antiviral drugs (80% nirmatrelvir, 20% molnupiravir) after they had tested positive. As of Jan 15, 2024, 1637 (6·0%) patients had been admitted to hospital, and 243 (0·9%) had died (table).TableDemographic and clinical characteristics of the patient populationTotal (N=27 194)Administered XBB.1.5 vaccines (N=3315)Not administered XBB.1.5 vaccines (N=23 879)Administered oral antiviral drugs (N=12 387)Not administered oral antiviral drugs (N=14 807)Admission to hospital (N=1637)Death (N=243)Age (years)Mean (SD)57·5 (19·6)67·3 (14·7)56·2 (19·8)62·6 (15·5)53·3 (21·5)65·9 (17·7)76·8 (13·2)12–498917 (33%)428 (13%)8489 (36%)2423 (20%)6494 (44%)299 (18%)9 (3·7%)50– 646658 (24%)621 (19%)6037 (25%)3644 (29%)3014 (20%)317 (19%)31 (13%)65–745782 (21%)1169 (35%)4613 (19%)3436 (28%)2346 (16%)416 (25%)50 (21%)75–844210 (15%)815 (25%)3395 (14%)2219 (18%)1991 (13%)414 (25%)70 (29%)≥851627 (6%)282 (9%)1345 (6%)665 (5%)962 (7%)191 (12%)83 (34%)SexMale10 328 (38%)1366 (41%)8962 (38%)4819 (39%)5509 (37%)664 (41%)136 (56%)Female16 866 (62%)1949 (59%)14 917 (62%)7568 (61%)9298 (63%)973 (59%)107 (44%)Race and ethnicityNon-Hispanic white20 622 (76%)2848 (86%)17 774 (74%)10 187 (82%)10 435 (70%)1300 (79%)188 (77%)Other6572 (24%)467 (14%)6105 (26%)2200 (18%)4372 (30%)337 (21%)55 (23%)ResidencyOhio23 595 (87%)2948 (89%)20 647 (86%)10 674 (86%)12 921 (87%)1424 (87%)210 (86%)Other3599 (13%)367 (11%)3232 (14%)1713 (14%)1886 (13%)213 (13%)33 (14%)Documented infection or vaccination<6 months580 (2%)12 (1%)568 (2%)323 (3%)257 (2%)58 (4%)12 (5%)≥6 months26 614 (98%)3303 (99%)23 311 (98%)12 064 (97%)14 550 (98%)1579 (96%)231 (95%)ComorbiditiesRespiratory5941 (22%)735 (22%)5206 (22%)2591 (21%)3350 (23%)612 (37%)96 (40%)Immunocompromised1844 (6·8%)248 (7·5%)1596 (6·7%)776 (6·3%)1068 (7·2%)330 (20%)103 (42%)Cardiovascular11 676 (43%)1786 (54%)9890 (41%)5738 (46%)5938 (40%)1142 (70%)199 (82%)Diabetic4357 (16%)618 (19%)3739 (16%)2109 (17%)2248 (15%)466 (28%)81 (33%)Obese4140 (15%)474 (14%)3666 (15%)1969 (16%)2,171 (15%)431 (26%)37 (15%)Other non-respiratory13 423 (49%)1857 (56%)11 566 (48%)6228 (50%)7195 (49%)1264 (77%)223 (92%)None8433 (31%)797 (24%)7636 (32%)3344 (27%)5089 (34%)134 (8·2%)10 (4·1%)Risk of severe disease*High risk of progression to severe disease as defined by the National Institutes of Health.3High24 578 (90%)3231 (97%)21 347 (89%)12 387 (100%)12 191 (82%)1611 (98%)241 (99%)Low2616 (10%)84 (3%)2532 (11%)02616 (18%)26 (2%)2 (1%)Nirmatrelvir contraindicatedYes609 (2%)51 (2%)558 (2%)81 (1%)528 (4%)152 (9%)52 (21%)No26 585 (98%)3264 (98%)23 321 (98%)12 306 (99%)14 279 (96%)1485 (91%)191 (79%)Social vulnerability index†Social vulnerability index as defined by the Centres for Disease Control and Prevention scale.Low to low-medium18 109 (67%)2459 (74%)15 650 (66%)8933 (72%)9176 (62%)1030 (63%)149 (61%)High-medium to high9085 (33%)856 (26%)8229 (34%)3454 (28%)5631 (38%)607 (37%)94 (39%)Data are n (%), unless stated otherwise.* High risk of progression to severe disease as defined by the National Institutes of Health.3National Institutes of HealthCoronavirus disease 2019 (COVID-19) treatment guidelines.https://www.covid19treatmentguidelines.nih.gov/Date: Dec 20, 2023Date accessed: February 20, 2024Google Scholar† Social vulnerability index as defined by the Centres for Disease Control and Prevention scale. Open table in a new tab Data are n (%), unless stated otherwise. To estimate the effects of XBB.1.5 vaccines and antiviral drugs on progression to severe disease while adjusting for observed confounders, we fit a Cox proportional hazards model to the composite endpoint of admission to hospital and death (ie, time from SARS-CoV-2 infection to admission to hospital or death, whichever occurred first), with XBB.1.5 vaccination and antiviral treatment as exposure variables and with demographic factors, comorbidities, and previous infection or vaccination as covariates (appendix pp 2, 3). The hazard ratio (HR) for XBB.1.5 vaccination was estimated at 0·69 (95% CI 0·59–0·81), and the HR for antiviral treatment was 0·58 (0·52–0·65). Older age (ie, individuals older than 65 years) and immunocompromised conditions substantially increased the risk of progression to severe disease. The HR for XBB.1.5 vaccination reported here measured its effects on progression to severe disease in addition to initial protection against infection. The effectiveness of XBB.1.5 vaccination in reducing the joint risk of infection and progression to severe disease would be greater than its effectiveness in reducing the risk of progression to severe disease, provided that XBB.1.5 vaccination reduced the risk of infection. Under a Cox model with separate effects of the two drugs, the HR was 0·61 (95% CI 0·54–0·69) for nirmatrelvir and 0·50 (0·41–0·60) for molnupiravir. Additionally, the HR for antiviral treatment was 0·47 (0·34–0·64) in patients who had received XBB.1.5 vaccines and 0·59 (0·52–0·66) in those who had not. In patients aged 65 years or older, the HR was 0·66 (0·55–0·79) for XBB.1.5 vaccination and 0·52 (0·45–0·60) for antiviral treatment; in patients aged younger than 65 years, the HR was 0·82 (0·59–1·15) for XBB.1.5 vaccination and 0·69 (0·57–0·82) for antiviral treatment. In immunocompromised patients, the HR was 0·69 (95% CI 0·47–1·01) for XBB.1.5 vaccination and 0·37 (0·28–0·50) for antiviral treatment; in immunocompetent patients, the HR was 0·70 (0·58–0·83) for XBB.1.5 vaccination and 0·63 (0·56–0·71) for antiviral treatment. We also fit a Cox model to the endpoint of time from SARS-CoV-2 infection to death. For this endpoint, the HR was 0·59 (95% CI 0·35–0·98) for XBB.1.5 vaccination and 0·13 (0·08–0·20) for antiviral treatment. Under a Cox model with separate effects of the two drugs, the HR was 0·12 (0·07–0·22) for nirmatrelvir and 0·13 (0·06–0·30) for molnupiravir. This study showed that both XBB.1.5 vaccines and antiviral drugs reduced the risk of serious consequences of infection with SARS-CoV-2 omicron subvariants. XBB.1.5 vaccines should be considered by all individuals, especially those who are aged 65 years or older or are immunocompromised, and either molnupiravir or nirmatrelvir can be prescribed to patients with COVID-19 who are at high risk of progressing to severe disease, regardless of their XBB.1.5 vaccination status. The effectiveness of XBB.1.5 vaccines against severe COVID-19 in the period of EG.5, HV.1, and JN.1 subvariants predominance was similar to that of bivalent boosters in the period of BQ.1–BQ.1.1 and XBB–XBB.1.5 predominance.4Lin DY Xu Y Gu Y et al.Durability of bivalent boosters against new omicron subvariants.N Engl J Med. 2023; 388: 1818-1820Crossref PubMed Scopus (36) Google Scholar The effectiveness of nirmatrelvir and molnupiravir was also similar between the two periods.5Lin DY Abi Fadel F Huang S et al.Nirmatrelvir or molnupiravir use and severe outcomes from omicron infections.JAMA Netw Open. 2023; 6e2335077Crossref Scopus (8) Google Scholar This study was limited by confounding bias. However, we adjusted for major confounders, such as age and comorbidities. Although the study included a large number of patients from multiple US states, it would be worthwhile to examine data from other health systems and other countries. This research was partly supported by US National Institutes of Health (R01 HL149683 paid to D-YL and R01 GM152717 paid to XW). We declare no competing interests. SH and AM collected data. D-YL supervised data analysis, which SH conducted. SH and XW directly accessed and verified the underlying data. XW and AD provided oversight. D-YL drafted the manuscript. All authors reviewed and approved the final manuscript, had full access to all data in the study, and had final responsibility for the decision to submit for publication. Download .pdf (.97 MB) Help with pdf files Supplementary appendix