Infectious Disease

Olender, S.A., Perez, K.K., Go, A.S., Balani, B., Price-Haywood, E.G., Shah, N.S., Wang, S., Walunas, T.L., Swaminathan, S., Slim, J., Chin, B., De Wit, S., Ali, S.M., Soriano Viladomiu, A., Robinson, P., Gottlieb, R.L., Tsang, T.Y.O., Lee, I.H., Hu, H., Haubrich, R.H., Chokkalingam, A.P., Lin, L., Zhong, L., Bekele, B.N., Mera-Giler, R., Phulpin, C., Edgar, H., Gallant, J., Diaz-Cuervo, H., Smith, L.E., Osinusi, A.O., Brainard, D.M. and Bernardino, J.I. (2021). “Remdesivir for Severe Coronavirus Disease 2019 (COVID-19) Versus a Cohort Receiving Standard of Care.” Clin Infect Dis 73(11): e4166-e4174.

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BACKGROUND: We compared the efficacy of the antiviral agent, remdesivir, versus standard-of-care treatment in adults with severe coronavirus disease 2019 (COVID-19) using data from a phase 3 remdesivir trial and a retrospective cohort of patients with severe COVID-19 treated with standard of care. METHODS: GS-US-540-5773 is an ongoing phase 3, randomized, open-label trial comparing two courses of remdesivir (remdesivir-cohort). GS-US-540-5807 is an ongoing real-world, retrospective cohort study of clinical outcomes in patients receiving standard-of-care treatment (non-remdesivir-cohort). Inclusion criteria were similar between studies: patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, were hospitalized, had oxygen saturation ≤94% on room air or required supplemental oxygen, and had pulmonary infiltrates. Stabilized inverse probability of treatment weighted multivariable logistic regression was used to estimate the treatment effect of remdesivir versus standard of care. The primary endpoint was the proportion of patients with recovery on day 14, dichotomized from a 7-point clinical status ordinal scale. A key secondary endpoint was mortality. RESULTS: After the inverse probability of treatment weighting procedure, 312 and 818 patients were counted in the remdesivir- and non-remdesivir-cohorts, respectively. At day 14, 74.4% of patients in the remdesivir-cohort had recovered versus 59.0% in the non-remdesivir-cohort (adjusted odds ratio [aOR] 2.03: 95% confidence interval [CI]: 1.34-3.08, P < .001). At day 14, 7.6% of patients in the remdesivir-cohort had died versus 12.5% in the non-remdesivir-cohort (aOR 0.38, 95% CI: .22-.68, P = .001). CONCLUSIONS: In this comparative analysis, by day 14, remdesivir was associated with significantly greater recovery and 62% reduced odds of death versus standard-of-care treatment in patients with severe COVID-19. CLINICAL TRIALS REGISTRATION: NCT04292899 and EUPAS34303.

Zhang, L., Poorbaugh, J., Dougan, M., Chen, P., Gottlieb, R.L., Huhn, G., Beasley, S., Daniels, M., Ngoc Vy Trinh, T., Crisp, M., Freitas, J.J., Vaillancourt, P., Patel, D.R., Nirula, A., Kallewaard, N.L., Higgs, R.E. and Benschop, R.J. (2021). “Endogenous Antibody Responses to SARS-CoV-2 in Patients With Mild or Moderate COVID-19 Who Received Bamlanivimab Alone or Bamlanivimab and Etesevimab Together.” Front Immunol 12: 790469.

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BACKGROUND: Neutralizing monoclonal antibodies (mAbs) to SARS-CoV-2 are clinically efficacious when administered early, decreasing hospitalization and mortality in patients with mild or moderate COVID-19. We investigated the effects of receiving mAbs (bamlanivimab alone and bamlanivimab and etesevimab together) after SARS-CoV-2 infection on the endogenous immune response. METHODS: Longitudinal serum samples were collected from patients with mild or moderate COVID-19 in the BLAZE-1 trial who received placebo (n=153), bamlanivimab alone [700 mg (n=100), 2800 mg (n=106), or 7000 mg (n=98)], or bamlanivimab (2800 mg) and etesevimab (2800 mg) together (n=111). A multiplex Luminex serology assay measured antibody titers against SARS-CoV-2 antigens, including SARS-CoV-2 protein variants that evade bamlanivimab or etesevimab binding, and SARS-CoV-2 pseudovirus neutralization assays were performed. RESULTS: The antibody response in patients who received placebo or mAbs had a broad specificity. Titer change from baseline against a receptor-binding domain mutant (Spike-RBD E484Q), as well as N-terminal domain (Spike-NTD) and nucleocapsid protein (NCP) epitopes were 1.4 to 4.1 fold lower at day 15-85 in mAb recipients compared with placebo. Neutralizing activity of day 29 sera from bamlanivimab monotherapy cohorts against both spike E484Q and beta variant (B.1.351) were slightly reduced compared with placebo (by a factor of 3.1, p=0.001, and 2.9, p=0.002, respectively). Early viral load correlated with the subsequent antibody titers of the native, unmodified humoral response (p<0.0001 at Day 15, 29, 60 and 85 for full-length spike). CONCLUSIONS: Patients with mild or moderate COVID-19 treated with mAbs develop a wide breadth of antigenic responses to SARS-CoV-2. Small reductions in titers and neutralizing activity, potentially due to a decrease in viral load following mAb treatment, suggest minimal impact of mAb treatment on the endogenous immune response.

Embi, P.J., Levy, M.E., Naleway, A.L., Patel, P., Gaglani, M., Natarajan, K., Dascomb, K., Ong, T.C., Klein, N.P., Liao, I.C., Grannis, S.J., Han, J., Stenehjem, E., Dunne, M.M., Lewis, N., Irving, S.A., Rao, S., McEvoy, C., Bozio, C.H., Murthy, K., Dixon, B.E., Grisel, N., Yang, D.H., Goddard, K., Kharbanda, A.B., Reynolds, S., Raiyani, C., Fadel, W.F., Arndorfer, J., Rowley, E.A., Fireman, B., Ferdinands, J., Valvi, N.R., Ball, S.W., Zerbo, O., Griggs, E.P., Mitchell, P.K., Porter, R.M., Kiduko, S.A., Blanton, L., Zhuang, Y., Steffens, A., Reese, S.E., Olson, N., Williams, J., Dickerson, M., McMorrow, M., Schrag, S.J., Verani, J.R., Fry, A.M., Azziz-Baumgartner, E., Barron, M.A., Thompson, M.G. and DeSilva, M.B. (2022). “Effectiveness of two-dose vaccination with mRNA COVID-19 vaccines against COVID-19-associated hospitalizations among immunocompromised adults-Nine States, January-September 2021.” Am J Transplant 22(1): 306-314.

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What is already known about this topic?
Studies suggest that immunocompromised persons who receive COVID-19 vaccination might not develop high neutralizing antibody titers or be as protected against severe COVID-19 outcomes as are immunocompetent persons.
What is added by this report?
The effectiveness of mRNA vaccination against laboratory-confirmed COVID-19–associated hospitalization was lower (77%) among immunocompromised adults than among immunocompetent adults (90%). Vaccine effectiveness varied considerably among immunocompromised patient subgroups.
What are the implications for public health practice?
Immunocompromised persons benefit from COVID-19 mRNA vaccination but are less protected from severe COVID-19 outcomes than are immunocompetent persons. Immunocompromised persons receiving mRNA COVID-19 vaccines should receive three doses and a booster, consistent with CDC recommendations, practice nonpharmaceutical interventions, and, if infected, be monitored closely and considered early for proven therapies that can prevent severe outcomes. [No abstract; excerpt from article].

Hughes, K., Middleton, D.B., Nowalk, M.P., Balasubramani, G.K., Martin, E.T., Gaglani, M., Talbot, H.K., Patel, M.M., Ferdinands, J.M., Zimmerman, R.K. and Silveira, F.P. (2021). “Effectiveness of Influenza Vaccine for Preventing Laboratory-Confirmed Influenza Hospitalizations in Immunocompromised Adults.” Clin Infect Dis 73(11): e4353-e4360.

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BACKGROUND: Yearly influenza immunization is recommended for immunocompromised (IC) individuals, although immune responses are lower than that for the nonimmunocompromised and the data on vaccine effectiveness (VE) in the IC is scarce. We evaluated VE against influenza-associated hospitalization among IC adults. METHODS: We analyzed data from adults ≥ 18 years hospitalized with acute respiratory illness (ARI) during the 2017-2018 influenza season at 10 hospitals in the United States. IC adults were identified using prespecified case definitions using electronic medical record data. VE was evaluated with a test-negative case-control design using multivariable logistic regression with polymerase chain reaction-confirmed influenza as the outcome and vaccination status as the exposure, adjusting for age, enrolling site, illness onset date, race, days from onset to specimen collection, self-reported health, and self-reported hospitalizations. RESULTS: Of 3524 adults hospitalized with ARI, 1210 (34.3%) had an immunocompromising condition. IC adults were more likely to be vaccinated than non-IC (69.5% vs 65.2%) and less likely to have influenza (22% vs 27.8%). The mean age did not differ among IC and non-IC (61.4 vs 60.8 years of age). The overall VE against influenza hospitalization, including immunocompetent adults, was 33% (95% confidence interval [CI], 21-44). VE among IC vs non-IC adults was lower at 5% (95% CI, -29% to 31%) vs 41% (95% CI, 27-52) (P < .05 for interaction term). CONCLUSIONS: VE in 1 influenza season was very low among IC individuals. Future efforts should include evaluation of VE among the different immunocompromising conditions and whether enhanced vaccines improve the suboptimal effectiveness among the immunocompromised.

Lewis, N.M., Naioti, E.A., Self, W.H., Ginde, A.A., Douin, D.J., Talbot, H.K., Casey, J.D., Mohr, N.M., Zepeski, A., Gaglani, M., Ghamande, S.A., McNeal, T.A., Shapiro, N.I., Gibbs, K.W., Files, D.C., Hager, D.N., Shehu, A., Prekker, M.E., Erickson, H.L., Gong, M.N., Mohamed, A., Henning, D.J., Steingrub, J.S., Peltan, I.D., Brown, S.M., Martin, E.T., Hubel, K., Hough, C.L., Busse, L.W., Ten Lohuis, C.C., Duggal, A., Wilson, J.G., Gordon, A.J., Qadir, N., Chang, S.Y., Mallow, C., Rivas, C., Babcock, H.M., Kwon, J.H., Exline, M.C., Halasa, N., Chappell, J.D., Lauring, A.S., Grijalva, C.G., Rice, T.W., Rhoads, J.P., Stubblefield, W.B., Baughman, A., Womack, K.N., Lindsell, C.J., Hart, K.W., Zhu, Y., Schrag, S.J., Kobayashi, M., Verani, J.R., Patel, M.M. and Tenforde, M.W. (2021). “Effectiveness of mRNA vaccines in preventing COVID-19 hospitalization by age and burden of chronic medical conditions among immunocompetent US adults, March-August 2021.” J Infect Dis Dec 21;jiab619. [Epub ahead of print].

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In a multi-state network, vaccine effectiveness (VE) against COVID-19 hospitalizations was evaluated among immunocompetent adults (≥18-years) during March-August 2021 using a case-control design. Among 1669 hospitalized COVID-19 cases (11% fully vaccinated) and 1950 RT-PCR-negative controls (54% fully vaccinated), VE was higher at 96% (95% CI: 93-98%) among patients with no chronic medical conditions than patients with ≥3 categories of conditions (83% [95% CI: 76-88%]). VE was similar between those aged 18-64 years vs ≥65 years (p>0.05). Vaccine effectiveness against severe COVID-19 was very high among adults without chronic conditions and lessened with increasing burden of comorbidities.