key: cord-0705047-recca75k
authors: Jurgens, Eric Matthew; Ketas, Thomas Joseph; Zhao, Zhen; Joseph Satlin, Michael; Small, Catherine Butkus; Sukhu, Ashley; Francomano, Erik; Klasse, Per Johan; Garcia, Arcania; Nguyenduy, Emeline; Bhavsar, Erica; Formenti, Silvia; Furman, Richard; Moore, John Philip; Leonard, John Paul; Martin, Peter
title: Serologic response to mRNA COVID‐19 vaccination in lymphoma patients
date: 2021-08-24
journal: Am J Hematol
DOI: 10.1002/ajh.26322
sha: f4c7262331b42aa37e18acf25dc5fadb9d30452b
doc_id: 705047
cord_uid: recca75k

nan

To the Editor:

The development of effective COVID-19 vaccines has been essential in slowing the spread of SARS-CoV-2. However, unvaccinated populations as well as those who do not respond to vaccination still remain at risk. Very few cancer patients were included in the COVID-19 mRNA vaccine trials and any individuals receiving chemotherapy or immunotherapy within 6 months were excluded. 1 Consequently, we have an inadequate knowledge of how well these vaccines work in the cancer patient population. However, by extrapolation from other vaccines, we hypothesized that patients with hematologic malignancies, especially those on immunosuppressive therapy, would produce poor serological responses to a COVID-19 vaccine. 2 In this single-center, observational cohort study we assessed antibody responses in lymphoma patients receiving a COVID-19 mRNA vaccine (BNT162b2, BioNTech/Pfizer, Germany/New York, NY; or mRNA-1273, Moderna, Cambridge, MA). All patients provided written informed consent to participate in observational research, and this study was approved by the Weill Cornell Medicine institutional review board (IRB 21-02023288). Serum samples were obtained before (when possible) and after vaccination. Post-vaccination samples were collected within 11-70 days of the second dose (median 24.5 days). In the healthcare worker (HCW) control group, the post-vaccination samples were obtained within 10-68 days of the second dose (median 40 days) (- Figure S1 ). We also include data from a healthy control group of 35 HCWs enrolled in the NYP-WELCOME (WEilL COrnell Medicine Employees) observational trial (IRB 20-04021831). The use of this cohort in an mRNA vaccine study as well as the assay to quantify immunoglobulin G (IgG) antibodies to the SARS-CoV-2 S-protein has been described previously. 3 Additionally, we determined whether any patients had serum antibodies to the SARS-CoV-2 nucleocapsid (N) protein, a marker for prior infection.

The anti-S protein response to mRNA vaccination was assessed by enzyme-linked immunosorbent assay using sera from 67 patients with lymphoma and 35 healthy HCW controls. The majority of patients in this study were white (74.6%, Table S1 ). The median age of the study group was 71 (24-90). The most common comorbidities were hypertension (37.3%) and hyperlipidemia (50.7%). We studied the CLL and other NHL patients in more detail to understand the implications of their treatment (Figure 1(B) ). Every treatmentnaïve and remote-therapy (no treatment in over 24 months) CLL patient responded to vaccination, whereas only 40% (6/15) of those currently being treated had anti-S protein titers above the designated cut-off value. We next studied the relationship between when anti-CD20 mAb therapy ceased and the vaccine response (Figure 1(C) ). None of the 11 CLL and other NHL patients receiving this treatment within 6 months of vaccination had anti-S protein titers above the cut-off, but longer intervals were associated with higher titers. Thus, CLL and other NHL patients who were last treated >24 months before vaccination had response rates of 66.7% (6/9) and 71.4% (10/14), respectively. It is notable that 3/3 CLL and 3/4 other NHL non-responders in this subgroup were receiving a different type of active therapy at the time of vaccination (Table S6 ). We suggest that even when anti-CD20 mAb therapy ceased >24 months before vaccination, other forms of ongoing active therapy can compromise the vaccine response.

Thus we demonstrated that commonly used lymphoma therapies can adversely influence the performance of COVID-19 vaccines, with anti-CD20 mAbs having the greatest impact. With regard to anti-CD20 mAbs, our results are consistent with a growing number of reports that patients on active, or with recent anti-CD20 mAb treatment do not respond to vaccination. [4] [5] [6] Compared with other studies, we report a higher rate of seroconversion in patients on active BTKi monotherapy. 4, 5 Here, we found that 66.7% (4/6) of CLL patients and 50% (2/4) of other NHL patients did develop high-titer IgG antibodies after mRNA vaccination. In a study by Herishanu et al. 4 only 16% (8/50) of CLL patients treated with a BTKi responded to vaccination with BNT162b2. In our study, CLL responders on BTKi monotherapy were on treatment for a median length of 53.5 (23-74) months prior to the first vaccine dose. In comparison, CLL non-responders on BTKi monotherapy were on treatment for a median of 2 (1-3) months. The CLL responders were described as having a good response to BTKi monotherapy, with two patients in complete remission and two patients with no progression of disease. All CLL responders were compliant with treatment and only one patient had a recent interruption in therapy. This patient was hospitalized for COVID-19 in April 2020 and treatment was held for approximately 3 weeks after which therapy was restarted. In this study, he was found to be anti-N-positive, consistent with pre-existing serologic immunity from prior infection.

Finally, we studied the avidity of IgG antibodies to the Receptor Binding Domain in the lymphoma and healthy control patients ( Figure S1 ). The avidity was significantly higher (p < 0.0001) for anti-N-positive lymphoma patients than for anti-N-negative lymphoma patients as well as healthy controls, all of whom were anti-N-negative ( Figure S1(A) ). These findings suggest COVID-19 convalescent patients (i.e., anti-N positive) have had longer to affinity mature their anti-S antibodies, which are boosted by the mRNA vaccines. We noted that patients currently receiving venetoclax or a BTKi had lower avidity S-protein antibodies than the other groups, although the group sizes were too small for statistical significance ( Figure S1(B) ).

In conclusion, we found that most lymphoma patients respond to vaccination with an mRNA-based COVID-19 vaccine, but a substantial fraction (>40%) do not and therefore may remain at risk of infection and disease. There were no significant differences in the S-protein IgG antibody response rates or titers between the different lymphoma histologic subtypes. Treatment status was, however, a relevant variable. Treatment-naïve lymphoma patients responded to vaccination in a similar manner to the HCW group, as did patients who had not received therapy for at least 2 years.

However, this controlled study presents compelling evidence that patients on active therapy for lymphoma may not respond to vaccination. Our results are particularly concerning for patients on anti-CD20 mAb therapy, given that no patients who had received treatment within 6 months responded well to mRNA vaccination.

Thus these patients probably remain at risk of infection with SARS-CoV-2. In this patient population, we suggest exploring alternative strategies for protection such as passive immunization with anti-S monoclonal antibody therapy or, if possible, delaying therapy until after vaccination.

Commentary: SARS-CoV-2 vaccines and cancer patients

Vaccinations in CLL: implications for COVID-19

Antibody responses to SARS-CoV-2 mRNA vaccines are detectable in saliva

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia

Antibody response to SARS-CoV-2 vaccines in patients with hematologic malignancies

Seroconversion rates following COVID-19 vaccination among patients with cancer