Fatal breakthrough infection after anti-BCMA CAR-T therapy highlights suboptimal immune response to SARS-CoV-2 vaccination in myeloma patients (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly effective in healthy individuals. Patients with multiple myeloma (MM) are immunocompromised due to defects in humoral and cellular immunity as well as immunosuppressive therapies. The efficacy after two doses of SARS-CoV-2 mRNA vaccination in MM patients is currently unknown. Here, we report the case of a MM patient who developed a fatal SARS-CoV-2 infection after full vaccination while in remission after B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T treatment. We show that the patient failed to generate antibodies or SARS-CoV-2-specific B and T cell responses, highlighting the continued risk of severe coronavirus disease 2019 (COVID-19) in vaccine non-responders. In the largest cohort of vaccinated MM patients to date, we demonstrate that 15.9% lack SARS-CoV-2 spike antibody response more than 10 days after the second mRNA vaccine dose. The patients actively receiving MM treatment, especially on regimens containing anti-CD38 and anti-BCMA, have lower antibody responses compared to healthy controls. Thus, it is of critical importance to monitor this patient population for serological responses. Non-responders may benefit from ongoing public health measures and from urgent study of prophylactic treatments to prevent SARS-CoV-2 infection.

SARS-CoV-2 infection induces robust, neutralizing antibody responses that are stable for at least three months (preprint)

SARS-CoV-2 has caused a global pandemic with millions infected and numerous fatalities. Questions regarding the robustness, functionality and longevity of the antibody response to the virus remain unanswered. Here we report that the vast majority of infected individuals with mild-to-moderate COVID-19 experience robust IgG antibody responses against the viral spike protein, based on a dataset of 19,860 individuals screened at Mount Sinai Health System in New York City. We also show that titers are stable for at least a period approximating three months, and that anti-spike binding titers significantly correlate with neutralization of authentic SARS-CoV-2. Our data suggests that more than 90% of seroconverters make detectible neutralizing antibody responses and that these titers are stable for at least the near-term future.

Neutralizing Antibody Responses in COVID-19 Convalescent Sera (preprint)

Passive transfer of antibodies from COVID-19 convalescent patients is being used as an experimental treatment for eligible patients with SARS-CoV-2 infections. The United States Food and Drug Administrations (FDA) guidelines for convalescent plasma recommends target antibody titers of 160. We evaluated SARS-CoV-2 neutralizing antibodies in sera from recovered COVID-19 patients using plaque reduction neutralization tests (PRNT) at low (PRNT50) and high (PRNT90) stringency thresholds. We found that neutralizing activity increased with time post symptom onset (PSO), reaching a peak at 31-35 days PSO. At this point, the number of sera having neutralizing titers of at least 160 was [~]93% (PRNT50) and [~]54% (PRNT90). Sera with high SARS-CoV-2 antibody levels (>960 ELISA titers) showed maximal activity, but not all high titer sera contained neutralizing antibody at FDA recommended levels, particularly at high stringency. These results underscore the value of serum characterization for neutralization activity.

SARS-CoV-2 Viral Load Predicts COVID-19 Mortality (preprint)

The need for reliable and widely available SARS-CoV-2 testing is well recognized, but it will be equally necessary to develop quantitative methods that determine viral load in order to guide patient triage and medical decision making. We are the first to report that SARS-CoV-2 viral load at the time of presentation is an independent predictor of COVID-19 mortality in a large patient cohort (n=1,145). Viral loads should be used to identify higher-risk patients that may require more aggressive care and should be included as a key biomarker in the development of predictive algorithms.

Prevalence of SARS-CoV-2 Antibodies Among Healthcare Workers at a Tertiary Academic Hospital in New York City (preprint)

Background: SARS-CoV-2 antibody testing is important for understanding immunity prevalence, and may have implications for healthcare workers (HCW) during the SARS-CoV-2 pandemic. Methods: We conducted immunologic testing of healthcare workers to determine the prevalence of SARS-CoV-2 IgG in this population. HCW were advised to wait at least two weeks from time of symptom onset or suspected exposure before undergoing testing. All participants were self-reported asymptomatic for at least three days at the time of testing. Results: Two hundred eighty-five samples were collected from March 24, 2020 to April 4, 2020. The average age of participants was 38 years (range 18-84), and 54% were male. Thirty-three percept tested IgG positive, 3% tested weakly positive, and 64% tested negative. Neither age nor sex was associated with antibody development. Conclusion: Thirty-six percent of HCW had IgG antibodies to SARS-CoV-2, reflecting the high exposure of inpatient and ambulatory frontline staff to this viral illness, most of whom had minimal symptoms and were working in the weeks preceding testing. While we continue to recommend standard protective precautions per CDC guidelines for all HCW, HCW with SARS-CoV-2 IgG may become our safest frontline providers as we learn if our IgG antibodies confer immunity. Knowing IgG antibody status may ease concerns regarding personal risk as this pandemic continues.

Convalescent plasma treatment of severe COVID-19: A matched control study (preprint)

Background Since December 2019, Coronavirus Disease 2019 (COVID-19) has become a global pandemic, causing mass morbidity and mortality. Prior studies in other respiratory infections suggest that convalescent plasma transfusion may offer benefit to some patients. Here, the outcomes of thirty-nine hospitalized patients with severe to life-threatening COVID-19 who received convalescent plasma transfusion were compared against a cohort of retrospectively matched controls. Methods Plasma recipients were selected based on supplemental oxygen needs at the time of enrollment and the time elapsed since the onset of symptoms. Recipients were transfused with convalescent plasma from donors with a SARS-CoV-2 (severe acute respiratory disease coronavirus 2) anti-spike antibody titer of [≥]1:320 dilution. Matched control patients were retrospectively identified within the electronic health record database. Supplemental oxygen requirements and survival were compared between plasma recipients and controls. Results Convalescent plasma recipients were more likely than control patients to remain the same or have improvements in their supplemental oxygen requirements by post-transfusion day 14, with an odds ratio of 0.86 (95% CI: 0.75~0.98; p=0.028). Plasma recipients also demonstrated improved survival, compared to control patients (log-rank test: p=0.039). In a covariates-adjusted Cox model, convalescent plasma transfusion improved survival for non-intubated patients (hazard ratio 0.19 (95% CI: 0.05 ~0.72); p=0.015), but not for intubated patients (1.24 (0.33~4.67); p=0.752). Conclusions Convalescent plasma transfusion is a potentially efficacious treatment option for patients hospitalized with COVID-19; however, these data suggest that non-intubated patients may benefit more than those requiring mechanical ventilation.

Humoral immune response and prolonged PCR positivity in a cohort of 1343 SARS-CoV 2 patients in the New York City region (preprint)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The percentage of infected individuals who seroconvert is still an open question. In addition, it has been shown in some individuals that viral genome can still be detected at considerable time post symptom resolution. Here we investigated both seroconversion and PCR-positivity in a large cohort of convalescent serum donors in New York City. Methods: Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via enzyme-linked immunosorbent assay for presence of anti SARS-CoV-2 spike antibodies. Results: All but three confirmed SARS-CoV-2 patients seroconverted to the SARS-CoV-2 spike while only 37.4% of suspected SARS-CoV-2 patients seroconverted. PCR-positivity was detected up to 28 days from symptom resolution. Conclusions: Here we show that the vast majority of confirmed COVID19 patients seroconvert, potentially providing immunity to reinfection. We also report that in a large proportion of individuals, viral genome can be detected via PCR in the upper respiratory tract for weeks post symptom resolution, but it is unclear if this signal represents infectious virus.