BNT162b2 XBB1.5-adapted Vaccine and COVID-19 Hospital Admissions and Ambulatory Visits in US Adults (preprint)

ImportanceData describing the early additional protection afforded by recently recommended XBB1.5- adapted COVID-19 vaccines are limited. ObjectiveWe estimated the association between receipt of BNT162b2 XBB1.5-adapted vaccine (Pfizer- BioNTech 2023-2024 formulation) and medically attended COVID-19 outcomes among adults [≥]18 years of age. Design, Setting, and ParticipantsWe performed a test-negative case-control study to compare the odds of BNT162b2 XBB1.5- adapted vaccine receipt between COVID-19 cases and test-negative controls among adults in the Kaiser Permanente Southern California health system between October 11 and December 10, 2023. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression models that were adjusted for patient demographic and clinical characteristics. ExposureThe primary exposure was receipt of BNT162b2 XBB1.5-adapted vaccine compared to not receiving an XBB1.5-adapted vaccine of any kind, regardless of prior COVID-19 vaccination or SARS-CoV-2 infection history. We also compared receipt of prior (non-XBB1.5-adapted) versions of COVID-19 vaccines to the unvaccinated to estimate remaining protection from older vaccines. Main Outcomes and MeasuresCases were those with a positive SARS-CoV-2 polymerase chain reaction test, and controls tested negative. Analyses were done separately for COVID-19 hospital admissions, emergency department (ED) and urgent care (UC) encounters, and outpatient visits. ResultsAmong 4232 cases and 19,775 controls with median age of 54 years, adjusted ORs for testing positive for SARS-CoV-2 among those who received BNT162b2 XBB1.5-adapted vaccine a median of 30 days ago (vs not having received an XBB1.5-adapted vaccine of any kind) were 0.37 (95% CI: 0.20-0.67) for COVID-19 hospitalization, 0.42 (0.34-0.53) for ED/UC visits, and 0.42 (0.27-0.66) for outpatient visits. Compared to the unvaccinated, those who had received only older versions of COVID-19 vaccines did not show significantly reduced risk of COVID-19 outcomes, including hospital admission. Conclusions and RelevanceOur findings reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines given that (1) XBB1.5-adapted vaccines provided significant additional protection against a range of COVID-19 outcomes and (2) older versions of COVID-19 vaccines offered little, if any, additional protection, including against hospital admission, regardless of the number or type of prior doses received. KEY POINTS QuestionsDoes receiving the BNT162b2 XBB1.5-adapted vaccine offer additional protection against COVID-19 hospital admission and ambulatory visits in US adults [≥]18 years of age compared to not receiving an XBB1.5-adapted vaccine of any kind? Do older versions of COVID-19 vaccine still provide any protection compared to the unvaccinated? FindingsThe BNT162b2 XBB1.5-adapted vaccine (Pfizer-BioNTech 2023-2024 formulation) provided significant additional protection against a range of COVID-19 outcomes during a period when XBB sub-lineages were predominant but JN.1 was also co-circulating and rapidly increasing in prevalence. Older versions of COVID-19 vaccines offered little, if any, additional protection compared to the unvaccinated, including against COVID-19 hospital admission, regardless of the number or type of prior doses received. MeaningOur findings reaffirm current recommendations for broad age-based use of annually updated COVID-19 vaccines.

Antibody response to symptomatic infection with SARS-CoV-2 Omicron variant viruses, December 2021 to June 2022 (preprint)

To describe humoral immune responses to symptomatic SARS-CoV-2 infection, we assessed immunoglobulin G binding antibody levels using a commercial multiplex bead assay against SARS-CoV-2 ancestral spike protein receptor binding domain (RBD) and nucleocapsid protein (N). We measured binding antibody units per mL (BAU/mL) during acute illness within 5 days of illness onset and during convalescence in 105 ambulatory patients with laboratory-confirmed SARS-CoV-2 infection with Omicron variant viruses. Comparing acute- to convalescent phase antibody concentrations, geometric mean anti-N antibody concentrations increased 47-fold from 5.5 to 259 BAU/mL. Anti-RBD antibody concentrations increased 2.5-fold from 1258 to 3189 BAU/mL.

Anti-SARS-CoV-2 Antibody Levels Associated with COVID-19 Protection in Outpatients Tested for SARS-CoV-2, US Flu VE Network, October 2021 to June 2022 (preprint)

BackgroundWe assessed the association between antibody concentration [≤]5 days of symptom onset and COVID-19 illness among patients enrolled in a test-negative study MethodsFrom October 2021[boxh]June 2022, study sites in seven states enrolled and tested respiratory specimens from patients of all ages presenting with acute respiratory illness for SARS-CoV-2 infection using rRT-PCR. In blood specimens, we measured concentration of anti- SARS-CoV-2 antibodies against the ancestral strain spike protein receptor binding domain (RBD) and nucleocapsid (N) antigens in standardized binding antibody units (BAU/mL). Percent reduction in odds of symptomatic COVID-19 by anti-RBD antibody was estimated using logistic regression modeled as (1-adjusted odds ratio of COVID-19)x100, adjusting for COVID-19 vaccination status, age, site, and high-risk exposure. ResultsA total of 662 (33%) of 2,018 symptomatic patients tested positive for acute SARS- CoV-2 infection. During the Omicron-predominant period, geometric mean anti-RBD binding antibody concentrations measured 823 BAU/mL (95%CI:690[boxh]981) among COVID-19 case- patients versus 1,189 BAU/mL (95%CI:1,050[boxh]1,347) among SARS-CoV-2 test-negative patients. In the adjusted logistic regression, increasing levels of anti-RBD antibodies were associated with reduced odds of COVID-19 for both Delta and Omicron infections. ConclusionHigher anti-RBD antibodies in patients were associated with protection against symptomatic COVID-19 during emergence of SARS-CoV-2 Delta and Omicron variants.

Increased vaccine sensitivity of an emerging SARS-CoV-2 variant (preprint)

Host immune responses are a key source of selective pressure driving pathogen evolution. Emergence of many SARS-CoV-2 lineages has been associated with improvements in their ability to evade population immunity resulting from both vaccination and infection. Here we show diverging trends of escape from vaccine-derived and infection-derived immunity for the emerging XBB/XBB.1.5 Omicron lineage. Among 31,739 patients tested in ambulatory settings in Southern California from December, 2022 to February, 2023, adjusted odds of prior receipt of 2, 3, 4, and [≥]5 COVID-19 vaccine doses were 10% (95% confidence interval: 1-18%), 11% (3-19%), 13% (3-21%), and 25% (15-34%) lower, respectively, among cases infected with XBB/XBB.1.5 than among cases infected with other co-circulating lineages. Similarly, prior vaccination was associated with greater protection against progression to hospitalization among cases with XBB/XBB.1.5 than among non-XBB/XBB.1.5 cases (70% [30-87%] and 48% [7-71%], respectively, for recipients of [≥]4 doses). In contrast, cases infected with XBB/XBB.1.5 had 17% (11-24%) and 40% (19-65%) higher adjusted odds of having experienced 1 and [≥]2 prior documented infections, respectively, including with pre-Omicron variants. As immunity acquired from SARS-CoV-2 infection becomes increasingly widespread, fitness costs associated with enhanced vaccine sensitivity in XBB/XBB.1.5 may be offset by increased ability to evade infection-derived host responses.

Prior SARS-CoV-2 Infection and COVID-19 Vaccine Effectiveness against Outpatient Illness during Widespread Circulation of SARS-CoV-2 Omicron Variant, US Flu VE Network (preprint)

Background: We estimated combined protection conferred by prior SARS-CoV-2 infection and COVID-19 vaccination against COVID-19-associated acute respiratory illness (ARI). Methods: During SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variant circulation between October 2021 and April 2022, prospectively enrolled adult patients with outpatient ARI had respiratory and filter paper blood specimens collected for SARS-CoV-2 molecular testing and serology. Dried blood spots were tested for immunoglobulin-G antibodies against SARS-CoV-2 nucleocapsid (NP) and spike protein receptor binding domain antigen using a validated multiplex bead assay. Evidence of prior SARS-CoV-2 infection also included documented or self-reported laboratory-confirmed COVID-19. We used documented COVID-19 vaccination status to estimate vaccine effectiveness (VE) by multivariable logistic regression by prior infection status. Results: 455 (29%) of 1577 participants tested positive for SARS-CoV-2 infection at enrollment; 209 (46%) case-patients and 637 (57%) test-negative patients were NP seropositive, had documented previous laboratory-confirmed COVID-19, or self-reported prior infection. Among previously uninfected patients, three-dose VE was 97% (95% confidence interval [CI], 60%, 99%) against Delta, but not statistically significant against Omicron. Among previously infected patients, three-dose VE was 57% (CI, 20%, 76%) against Omicron; VE against Delta could not be estimated. Conclusions: Three mRNA COVID-19 vaccine doses provided additional protection against SARS-CoV-2 Omicron variant-associated illness among previously infected participants.

Association of SARS-CoV-2 BA.4/BA.5 Omicron lineages with immune escape and clinical outcome (preprint)

Expansion of the SARS-CoV-2 BA.4/BA.5 Omicron lineages in populations with prevalent immunity from prior infection and vaccination has raised concerns about the association of these lineages with immune escape. Here we show that COVID-19 vaccination and documented prior infection are associated with reduced protection against infection with BA.4/BA.5. Compared to time-matched BA.2 cases, BA.4/BA.5 cases had 9% (95% confidence interval: 2-17%) and 27% (15-41%) higher adjusted odds of having received 3 and 4 COVID-19 vaccine doses, respectively, and 55% (39-71%) higher adjusted odds of documented infection [≥]90 days previously. However, BA.4/BA.5 infection was not associated with differential risk of emergency department presentation, hospital admission, or intensive care unit admission following an initial outpatient diagnosis. This finding held after correcting for potential exposure misclassification resulting from unascertained prior infections. Despite increased risk of BA.4/BA.5 breakthrough infection observed among previously vaccinated or infected individuals, the reduced severity associated with prior (BA.1 and BA.2) Omicron lineages has persisted with BA.4/BA.5.

Clinical outcomes among patients infected with Omicron (B.1.1.529) SARS-CoV-2 variant in southern California (preprint)

The Omicron (B.1.1.529) variant of SARS-CoV-2 rapidly achieved global dissemination following its emergence in southern Africa in November, 2021.1,2 Epidemiologic surveillance has revealed changes in COVID-19 case-to-hospitalization and case-to-mortality ratios following Omicron variant emergence,3-6 although interpretation of these changes presents challenges due to differential protection against Omicron or Delta (B.1.617.2) variant SARS-CoV-2 infections associated with prior vaccine-derived and naturally-acquired immunity, as well as longer-term changes in testing and healthcare practices.7 Here we report clinical outcomes among 222,688 cases with Omicron variant infections and 23,305 time-matched cases with Delta variant infections within the Kaiser Permanente Southern California healthcare system, who were followed longitudinally following positive outpatient tests between 15 December, 2021 and 17 January, 2022, when Omicron cases were almost exclusively BA.1 or its sublineages. Adjusted hazard ratios of progression to any hospital admission, symptomatic hospital admission, intensive care unit admission, mechanical ventilation, and death were 0.59 (95% confidence interval: 0.51-0.69), 0.59 (0.51-0.68), 0.50 (0.29-0.87), 0.36 (0.18-0.72), and 0.21 (0.10-0.44) respectively, for cases with Omicron versus Delta variant infections. In contrast, among 14,661 Omicron cases ascertained by outpatient testing between 3 February and 17 March, 2022, infection with the BA.2 or BA.1/BA.1.1 subvariants did not show evidence of differential risk of severe outcomes. Lower risk of severe clinical outcomes among cases with Omicron variant infection merits consideration in planning of healthcare capacity needs amid establishment of the Omicron variant as the dominant circulating SARS-CoV-2 lineage globally, and should inform the interpretation of both case- and hospital-based surveillance data.