Abstract In some immunocompromised patients with chronic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, considerable adaptive evolution occurs. Some substitutions found in chronic infections are lineage-defining mutations in variants of concern (VOCs), which has led to the hypothesis that VOCs emerged from chronic infections. In this study, we searched for drivers of VOC-like emergence by consolidating sequencing results from a set of 27 chronic infections. Most substitutions in this set reflected lineage-defining VOC mutations; however, a subset of mutations associated with successful global transmission was absent from chronic infections. We further tested the ability to associate antibody evasion mutations with patient-specific and virus-specific features and found that viral rebound is strongly correlated with the emergence of antibody evasion. We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient’s body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence. 

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Drivers of adaptive evolution during chronic SARS-CoV-2 infections

Immunosuppressed patients have increased risk for morbidity and mortality from COVID-19 because they less frequently mount antibody responses to vaccines and often cannot tolerate small-molecule antivirals. The Omicron variant of concern of SARS-CoV-2 has progressively defeated anti-Spike mAbs authorized so far, paving the way to a return to COVID-19 convalescent plasma (CCP) therapy. In this systematic review we performed a metanalysis of 6 controlled studies (including 2 randomized controlled trials; totaling 368 treated patients and 1119 control), an individual patient data analysis of 125 case reports/series (totaling 265 patients), and a descriptive analysis of 13 uncontrolled large case series without individual patient data available (totaling 358 patients). The metanalysis showed a risk ratio for mortality of 0.61 in treatment with CCP versus standard of care for immunosuppressed COVID-19 patients. On the basis of this evidence, we encourage initiation of high-titer CCP from vaccinees (hybrid plasma) in immunocompromised patients.

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COVID-19 Convalescent Plasma for the Treatment of Immunocompromised Patients: A Systematic Review and Meta-analysis

Importance Patients who are immunocompromised have increased risk for morbidity and mortality associated with coronavirus disease 2019 (COVID-19) because they less frequently mount antibody responses to vaccines. Although neutralizing anti-spike monoclonal-antibody treatment has been widely used to treat COVID-19, evolutions of SARS-CoV-2 have been associated with monoclonal antibody-resistant SARS-CoV-2 variants and greater virulence and transmissibility of SARS-CoV-2. Thus, the therapeutic use of COVID-19 convalescent plasma has increased on the presumption that such plasma contains potentially therapeutic antibodies to SARS-CoV-2 that can be passively transferred to the plasma recipient. Objective To assess the growing number of reports of clinical experiences of patients with COVID-19 who are immunocompromised and treated with specific neutralizing antibodies via COVID-19 convalescent plasma transfusion. Data Sources On August 12, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma use in patients who are immunocompromised. Study Selection Randomized clinical trials, matched cohort studies, and case report or series on COVID-19 convalescent plasma use in patients who are immunocompromised were included. The electronic search yielded 462 unique records, of which 199 were considered for full-text screening. Data Extraction and Synthesis The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 3 independent reviewers in duplicate and pooled. Main Outcomes and Meaures The prespecified end point was all-cause mortality after COVID-19 convalescent plasma transfusion; exploratory subgroup analyses were performed based on putative factors associated with the potential mortality benefit of convalescent plasma. Results This systematic review and meta-analysis included 3 randomized clinical trials enrolling 1487 participants and 5 controlled studies. Additionally, 125 case series or reports enrolling 265 participants and 13 uncontrolled large case series enrolling 358 participants were included. Separate meta-analyses, using models both stratified and pooled by study type (ie, randomized clinical trials and matched cohort studies), demonstrated that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for the amalgam of both randomized clinical trials and matched cohort studies (risk ratio [RR], 0.63 [95% CI, 0.50-0.79]). Conclusions and Relevance These findings suggest that transfusion of COVID-19 convalescent plasma is associated with mortality benefit for patients who are immunocompromised and have COVID-19. 

The COVID-19 pandemic has been accompanied by SARS-CoV-2 evolution and emergence of viral variants that have far exceeded initial expectations. Five major variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) have emerged, each having both unique and overlapping amino acid substitutions that have affected transmissibility, disease severity, and susceptibility to natural or vaccine-induced immune responses and monoclonal antibodies. Several of the more recent variants appear to have evolved properties of immune evasion, particularly in cases of prolonged infection. Tracking of existing variants and surveillance for new variants are critical for an effective pandemic response. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

https://www.annualreviews.org/doi/pdf/10.1146/annurev-med-042921-020956

COVID-19: Challenges of Viral Variants.

On Dec 20, 2020, the Israeli Ministry of Health launched a national COVID-19 vaccination campaign aiming to rapidly vaccinate all adults using the Pfizer–BioNtech BNT162b2 mRNA vaccine given in two doses 21 days apart, and by June, 2021, following US Food and Drug Administration (FDA) approval, it was expanded to children and adolescents aged 12–16 years. By July 1, 2021, 5 184 169 Israelis (56·2% of the population) were fully vaccinated. Although patients with cancer were excluded from the pivotal BNT162b2 vaccine trials, a series of studies examined the safety and efficacy of the vaccine in patients with solid tumours; all showed consistent data,1Waldhorn I Holland R Goshen-Lago T et al.Six-month efficacy and toxicity profile of BNT162b2 vaccine in cancer patients with solid tumors.Cancer Discov. 2021; 11: 2430-2435Crossref PubMed Scopus (6) Google Scholar, 2Eliakim-Raz N Massarweh A Stemmer A Stemmer SM Durability of response to SARS-CoV-2 BNT162b2 vaccination in patients on active anticancer treatment.JAMA Oncol. 2021; 7: 1716-1718Crossref PubMed Scopus (9) Google Scholar, 3Ligumsky H Safadi E Etan T et al.Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine among actively treated cancer patients.J Natl Cancer Inst. 2021; (published online Aug 28.)https://doi.org/10.1093/jnci/djab174Crossref PubMed Google Scholar, 4Waissengrin B Agbarya A Safadi E Padova H Wolf I Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors.Lancet Oncol. 2021; 22: 581-583Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar indicating the vaccine was safe and effective. At a median of 76 days after the second vaccine dose, 287 (88%) of 326 vaccine recipients who had cancer had protective antibody concentrations above the minimal threshold considered as seropositive, compared with 159 (97%) of 164 healthy individuals.3Ligumsky H Safadi E Etan T et al.Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine among actively treated cancer patients.J Natl Cancer Inst. 2021; (published online Aug 28.)https://doi.org/10.1093/jnci/djab174Crossref PubMed Google Scholar However, absolute antibody concentrations were significantly lower in patients with cancer (931 AU/mL), compared with healthy individuals (2817 AU/mL; p=0·003).3Ligumsky H Safadi E Etan T et al.Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine among actively treated cancer patients.J Natl Cancer Inst. 2021; (published online Aug 28.)https://doi.org/10.1093/jnci/djab174Crossref PubMed Google Scholar By July, 2021, Israel witnessed a resurgence of COVID-19 infections and severe illness, attributed to emergence of the delta (B.1.617.2) variant, but also to waning immunity of the vaccine.5Goldberg Y Mandel M Bar-On YM et al.Waning immunity after the BNT162b2 vaccine in Israel.N Engl J Med. 2021; 385: e85Crossref PubMed Scopus (24) Google Scholar Thus, on July 30, 2021, the Israeli Ministry of Health approved administration of a third (booster) dose of the BNT162b2 vaccine. This strategy proved to be highly effective6Bar-On YM Goldberg Y Mandel M et al.Protection of BNT162b2 vaccine booster against COVID-19 in Israel.N Engl J Med. 2021; 385: 1393-1400Crossref PubMed Scopus (92) Google Scholar and helped pave the way for a US FDA emergency authorisation of a booster dose for individuals aged 65 years and older or those aged 18–64 years at high risk of severe COVID-19.7US Food and Drug AdministrationFDA authorizes booster dose of Pfizer-BioNTech COVID-19 vaccine for certain populations.https://www.fda.gov/news-events/press-announcements/fda-authorizes-booster-dose-pfizer-biontech-covid-19-vaccine-certain-populationsDate: 2021Date accessed: November 4, 2021Google Scholar Between Aug 1, 2021, and Sept 29, 2021, we prospectively assessed the safety and immunogenicity of the booster dose, 1 month after its administration, in a cohort of 72 actively treated patients with cancer, compared with a matched group of 144 healthy individuals. During this period, adult patients with solid tumours, with no known past SARS-CoV-2 infection, receiving active treatment (defined as any intravenous anticancer medication, administered up to 3 weeks before the administration of the booster to up to 3 weeks afterwards) at the day care centre of the Oncology Division of Tel-Aviv Sourasky Medical Center (TASMC) were invited to participate in the study. The control group consisted of fully vaccinated health-care workers at TASMC with no personal history of cancer, active immune suppressive medications, or a documented past infection with SARS-CoV-2, who participated in a parallel study conducted simultaneously.8Saiag E Goldshmidt H Sprecher E Ben-Ami R Bomze D Immunogenicity of a BNT162b2 vaccine booster in health-care workers.Lancet Microbe. 2021; 2: e650Summary Full Text Full Text PDF PubMed Google Scholar Each patient with cancer who had received the third vaccine dose was matched by sex and year of birth to a healthy individual from among the TASMC cohort (for antibody response comparisons, patients were matched with two control participants). Seven patients were not matched by year of birth and instead were matched according to closest age (up to 8 years). Immunogenicity analysis was done using the SARS-CoV-2 IgG II Quant kit (Abbott, Sligo, Ireland) for patients with cancer9Tene Y Levytskyi K Adler A et al.An outbreak of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infections among hospital personnel with high mRNA vaccine uptake.Infect Control Hosp Epidemiol. 2021; (published online Sept 20.)https://doi.org/10.1017/ice.2021.412Crossref PubMed Scopus (0) Google Scholar and the ADVIA Centaur kit (Siemens Healthineers, Erlangen, Germany) for the control participants.8Saiag E Goldshmidt H Sprecher E Ben-Ami R Bomze D Immunogenicity of a BNT162b2 vaccine booster in health-care workers.Lancet Microbe. 2021; 2: e650Summary Full Text Full Text PDF PubMed Google Scholar Since each company has a different set of standard values for its respective antibody tests, WHO set a reference conversion method allowing comparison between the methods.10Siemens Healthcare Diagnostics IncUnderstanding SARS-CoV-2 IgG immunity thresholds and the process of standardization.https://cdn0.scrvt.com/39b415fb07de4d9656c7b516d8e2d907/b2406e708bf287c5/506564e9207f/Understanding-SARS-CoV-2-IgG-Immunity-Thresholds-and-the-Process-of-Standardization.pdfDate: 2021Date accessed: October 28, 2021Google Scholar We used this conversion method to compare between the tests used for the patients with cancer and the healthy control participants.8Saiag E Goldshmidt H Sprecher E Ben-Ami R Bomze D Immunogenicity of a BNT162b2 vaccine booster in health-care workers.Lancet Microbe. 2021; 2: e650Summary Full Text Full Text PDF PubMed Google Scholar, 9Tene Y Levytskyi K Adler A et al.An outbreak of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infections among hospital personnel with high mRNA vaccine uptake.Infect Control Hosp Epidemiol. 2021; (published online Sept 20.)https://doi.org/10.1017/ice.2021.412Crossref PubMed Scopus (0) Google Scholar, 10Siemens Healthcare Diagnostics IncUnderstanding SARS-CoV-2 IgG immunity thresholds and the process of standardization.https://cdn0.scrvt.com/39b415fb07de4d9656c7b516d8e2d907/b2406e708bf287c5/506564e9207f/Understanding-SARS-CoV-2-IgG-Immunity-Thresholds-and-the-Process-of-Standardization.pdfDate: 2021Date accessed: October 28, 2021Google Scholar The study was approved by the TASMC institutional review board. Following written informed consent, blood was withdrawn for immunogenicity analysis shortly before administration of the booster. Participants were contacted roughly 1 month after the booster, interviewed about side-effects, and asked to undergo repeat testing for immunogenicity analysis. The median age of the patients was 62 years (IQR 48–71); 65% of both groups were women (appendix p 1). Although the median time from second dose to third dose and time from second dose to first antibody testing were statistically significant longer in the healthy individuals compared with the patients with cancer (median time between dose two to three: 217 days (IQR 174–246) in healthy individuals vs 210 days (158–256) in patients with cancer [p<0·0001]; median time between dose two to first antibody test: 210 days (154–221) in healthy individuals vs 203 days (43–258) in patients with cancer [p<0·0001]), an absolute difference of 7 days was not deemed to have any clinical significance. The median time from third dose to second antigenicity testing was 33 days (IQR 21–44) in the patients with cancer compared with 27 days (23–29) in the control group (p=0·0056). 53 (75%) of 72 patients had metastatic disease and 45 (63%) received a chemotherapy-based regimens (appendix p 1). Before booster administration, 20 (28%) patients with cancer were found to be seronegative, compared with only two (1%) of the healthy individuals (p<0·0001; figure; appendix p 2). After administration of the booster, three patients with cancer and none of the healthy individuals remained seronegative (appendix p 2). A significant increase in anti-SARS-CoV-2S IgG absolute antibodies concentrations in both groups was also noted (p<0·0001 for the comparison of pre-booster and post-booster concentrations within each group). Yet, higher pre-booster and post-booster antibody concentrations were noted in healthy individuals than in patients with cancer (p=0·00011; figure; appendix p 2). Multivariate analysis, including study group (patient or control) and time (before or after third dose) adjusted for the matching factors (age and gender) indicated that the only statistically significant variable associated with increased titre levels was administration of the booster (p<0·0001; appendix p 2). Adverse effects were collected as previously described.4Waissengrin B Agbarya A Safadi E Padova H Wolf I Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors.Lancet Oncol. 2021; 22: 581-583Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar The vaccine was well tolerated among all participants. The most common side-effects in patients with cancer were local, including local pain at the injection site (35 [49%] of 72 patients) and local swelling (four [6%]; data not shown), whereas the most common systemic side-effects were fatigue (20 [28%]), fever (nine [13%]), headache (six [8%]), muscle pain (five [7%]), and chills (five [7%]). Although patients with cancer reported statistically significant less headache (p=0·0046), muscle pain (p<0·0001), and chills (p=0·026) than healthy controls, there were no statistically significant differences in the frequency of other side-effects (appendix p 3). No severe side-effects, either life-threatening or requiring hospitalisation or any other intervention, were reported. Because most patients with cancer in Israel were not known to have past SARS-CoV-2 infection, and because past infection might mask the response to vaccination, these patients who were known to have previous SARS-CoV-2 infection were excluded. Although this was a single-centre study, the TASMC is a large tertiary centre, treating more than 4500 new patients with solid tumours per year and serves as a national referral centre, with only 35% of the patients residing our immediate referral area. Thus, the study population is representative of the general population of Israeli patients with cancer on active treatment. Our presented data suggest a high rate of waning immunogenicity in patients with cancer approximately 6 months after the administration of the second dose of BNT162b2, and support the use of a booster dose in this vulnerable population of actively treated patients with cancer. The modest side-effect profile further supports this recommendation. Although the study cohort was relatively small, we believe that the explicit data from this population, combined with the robustness of the national data,5Goldberg Y Mandel M Bar-On YM et al.Waning immunity after the BNT162b2 vaccine in Israel.N Engl J Med. 2021; 385: e85Crossref PubMed Scopus (24) Google Scholar support the recommendation for a third dose booster for actively treated patients with cancer. YA declares receiving research grants from Pfizer, outside the scope of this work. AS is partially supported by the Israeli Council for Higher Education via the Weizmann Data Science Research Center, and by a research grant from the Estate of Tully and Michele Plesser. IW reports speaker fees and fees for consultancy from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Beyond Air, AstraZeneca, and Novartis; contracts or research funding from Roche, Novatis, Beyond Air, and Merck Sharp & Dohme; participation on a data safety monitoring board or advisory board of Merck Sharp & Dohme and AstraZeneca; participation in committee of Israeli Cancer Association; and stock options in Breath of life. All other authors declare no competing interests. COVI3 study investigators are listed at the appendix (p 4). Download .pdf (.29 MB) Help with pdf files Supplementary appendix 

Immunogenicity and safety of BNT162b2 mRNA vaccine booster in actively treated patients with cancer

Immunocompromised patients have an increased risk of persistent COVID-19 disease. We report here the clinical course of two patients with hematologic malignancies hospitalized due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In both patients, viral evolution including new spike gene mutations that occurred following treatment with anti-SARS-CoV-2 antibodies preparations, including convalescent plasma and bamlanivimab. These cases demonstrate the possibility of antibody-resistant SARS-CoV-2 infections evolution in immunocompromised patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmv.27445

Evolution of spike mutations following antibody treatment in two immunocompromised patients with persistent COVID-19 infection.

Real-world studies have demonstrated impressive effectiveness of the BNT162b2 COVID-19 vaccine in preventing symptomatic and asymptomatic SARS-CoV-2 infection. We describe an outbreak of SARS-CoV-2 infections in a hospital with high vaccine uptake. We found a low secondary attack rate (7%), suggesting low infectivity of vaccinated persons with vaccine breakthrough SARS-CoV-2 infections.

Katia Levytskyi

Papers

Evolution of spike mutations following antibody treatment in two immunocompromised patients with persistent COVID-19 infection.

An outbreak of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infections among hospital personnel with high mRNA vaccine uptake.