To the Editor:
The SARS‐CoV‐2 vaccines have been widely distributed based on remarkable efficacy
in immunocompetent patients. Unfortunately, there is a growing body of literature
indicating decreased efficacy in patients with lymphoma, particularly those receiving
B‐cell‐directed therapy.
1
Given high rates of morbidity and mortality, improving vaccine strategies is a critical
area of unmet need. Studies have shown improved immunogenicity in solid organ recipients
with a third mRNA vaccine.
2
This benefit was not as apparent in patients who lacked detectable antibodies after
the first two mRNA doses. While the Centers for Disease Control and Prevention (CDC)
currently recommends a third mRNA vaccine for immunocompromised patients, there is
considerable interest in alternative regimens. Due to concerns for thrombotic adverse
events and global supply limitations, some countries have utilized heterologous vaccination
strategies. Researchers in Europe and more recently, the United States, have demonstrated
significant increases in antibody levels with viral vector/mRNA vaccine combinations
in healthy individuals.
3
Data with heterologous vaccinations in people with defects in humoral and cellular
immunity, however, are limited. We have previously reported on successful seroconversion
with the Ad26.COV2.S viral vector vaccine (J&J) in a lymphoma patient after inadequate
response to two doses of the BNT162b2 mRNA vaccine (Pfizer/BioNTech).
4
Here, we present a larger series of B‐cell lymphoma patients who obtained J&J vaccines
after the standard two‐dose mRNA vaccine series. The majority of patients subsequently
received another mRNA vaccine for a total of four vaccinations.
As part of an IRB‐approved trial conducted at the University of Washington/Fred Hutchinson
Cancer Research Center, seven patients with low‐grade B‐cell lymphomas who had initially
received the two‐dose mRNA vaccination series and subsequently obtained a J&J viral
vector vaccine were identified. Patients had independently sought out heterologous
vaccination based on the lack of sufficient spike antibody response to the initial
two‐dose mRNA series, as assessed by the Roche Elecsys Anti‐SARS‐CoV‐2 S, a semiquantitative
total antibody assay against the spike protein receptor binding domain.
The median age was 62 years (range 41–79). Four were men and three were women. Lymphoma
subtypes included Waldenstrom's macroglobulinemia (WM, n = 3), follicular lymphoma
(FL, n = 3), and chronic lymphocytic leukemia (CLL, n = 1). (Table S1). Median spike
antibody level after completion of the initial two‐dose mRNA vaccination was < 0.4 AU/mL
(range < 0.4–0.6 AU/mL) as measured by the Roche Elecsys Anti‐SARS‐CoV‐2 S assay;
reference interval for a negative result was < 0.8 AU/mL. The median time between
the second dose of the mRNA vaccine and the J&J vaccine was 97 days (range 70–173).
Patients underwent one blood sample collection after receiving the J&J vaccine. Median
time from J&J to collection was 38 days (range 21–94). The median IgG, absolute lymphocyte
count, and normal CD19+ B‐cell counts were 597 mg/dL (range 180–1007), 0.97 × 103/mL
(range 0.61–2.56), and 0.6 cells/mL (range 0–121), respectively. Nucleocapsid antibody
was nonreactive in all patients, indicating no evidence of prior SARS‐CoV‐2 infection.
Utilizing the same Roche assay for semiquantitative anti‐spike binding antibody assessment,
three patients remained undetectable (< 0.4 AU/mL), two had a modest yet positive
response (2.6 and 5.3 AU/mL), and two experienced a greater seroconversion (118 and
207 AU/mL). (Figure 1). Positive responses were seen in a WM patient receiving zanubrutinib,
a CLL patient receiving ibrutinib, a FL patient 8 months after rituximab monotherapy,
and a FL patient 3 months after ibrutinib + venetoclax. Lack of response to J&J was
seen in two WM patients receiving zanubrutinib and an FL patient who completed obinutuzumab
and bendamustine 5 months prior. Patients who remained seronegative had a median normal
B‐cell count of 0 cells/mL (range 0–0.4) compared to 2.3 cells/mL (range 0.6–121)
in patients who became positive.
FIGURE 1
Serologic response with sequential vaccinations
After the CDC's recommendation for a third mRNA vaccine for immunocompromised patients,
five of the seven patients obtained a third mRNA vaccine and a fourth overall SARS‐CoV‐2
vaccine. Among this subgroup, four had seroconverted with J&J and one had not. Patients
underwent a second sample collection a median of 16 days after the fourth vaccine
(range 9–27). The four patients who originally seroconverted with J&J experienced
further increase in antibody level (range 290–19 970 AU/mL, Figure 1). The one patient
who did not seroconvert with J&J remained undetectable. None of the patients reported
significant adverse events.
It has become increasingly evident that the SARS‐CoV‐2 vaccines are ineffective for
many patients with lymphoid malignancies, due to their innate immune dysfunction and/or
receipt of B‐cell‐directed therapies. Given the increased risk of complications and
the prolongation of the pandemic, efforts must be focused on predicting who these
individuals are as well as understanding the complexities of their immune response
or lack thereof. A number of trials are investigating these questions, including collaborations
sponsored by the Leukemia and Lymphoma Society (LLS) and the CLL Global Research Foundation
(NCT04852822).
Here we present the first case series evaluating the use of a heterologous mRNA/vector/mRNA
vaccination strategy in patients with lymphoma. By serology assessment alone, the
use of a viral vector vaccine after the two‐dose mRNA series was successful in inducing
a response. Our results mirror a recent report from the LLS in which 9 of 17 seroconverted
with J&J after mRNA vaccination; resulting antibody levels ranged from 2.3 to 157
AU/mL using the same Roche assay.
5
A more robust response was seen in three who were seropositive prior to J&J (> 2500 AU/mL).
Interestingly, we also found that the addition of a fourth dose allowed for further
augmentation of the serologic response.
These findings are promising for vulnerable patients struggling to understand how
to exist in their environment. Determining exactly who this strategy will benefit,
however, is not possible from this small cohort. A number of variables such as type
of B‐cell directed therapy, length of and time from exposure, sequence of and duration
between vaccinations, and underlying disease biology may have had an impact. There
was a suggestion, though, that an absence of normal B‐cells may be predictive of inability
to mount an appropriate serologic response.
Given the paucity of data we look to the transplant literature for insight into other
vaccine‐induced immunologic changes, recognizing the differences in mechanisms of
immunosuppression, that is, calcineurin inhibitors and antimetabolites. In a German
study of solid organ recipients, researchers found that the vector/mRNA vaccine schedule
led to statistically significant increases in spike antibody levels, neutralization
antibody activity, and SARS‐CoV‐2‐reactive CD4 T‐cells, as well as a trend toward
increased numbers of CD8 T‐cells.
6
Unfortunately, the scope of our analysis did not allow for assessment of cellular
immune response.
In light of our findings, we are challenged with new questions. What are the immunologic
changes that allow for a viral vector/mRNA approach to be effective after failed response
to homologous mRNA vaccination? Does the improvement in serologic response correlate
with actual clinical benefit? For whom should a heterologous approach be considered
before a homologous approach? Is one type of vaccine better utilized for priming and
is that dependent on patient‐specific clinical features? And lastly, how can we improve
outcomes for a patient population who is often excluded from vaccine trials?
CONFLICT OF INTEREST
CU has received consultancy/honorarium from Abbvie, Astrazeneca, Atara, TG therapeutics,
Epizyme, Jansen, Pharmacyclics. She receives research funding from Abbvie, Pharmacyclics,
Astrazeneca, Kite/Gilead, Loxo/Lilly, Adaptive Biotechnologies. AG receives contract
revenue from Abbott and research funding from Gilead and Merck. MS receives consultancy/honoraria
or participates in advisory boards, steering committees or data safety monitoring
committees from Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene,
Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive
Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron and Atara
Biotherapeutics; research funding from Mustang Bio, Celgene, Bristol Myers Squibb,
Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis,
Atara Biotherapeutics, GenMab. JH received consultancy/honoraria from Gilead Sciences,
Amplyx, Allovir, Allogene therapeutics, CRISPR therapeutics, CSL Behring, OptumHealth,
Octapharma, and Takeda; and research funding from Takeda, Allovir, Karius, and Deverra
Therapeutics, and Gilead. RL receives research funding from Juno therapeutics, TG
Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, RAPT and received consultancy
from Morphosys. EW has no conflicts of interest. AG receives research funding from
Merck, I‐Mab bio, IgM Bio, Takeda, Gilead, Astra‐Zeneca, Agios, Janssen, BMS, SeaGen,
Teva; and consultancy/Honoraria from Incyte, Kite, Morphosys/Incyte, ADCT, Acrotech,
Merck, Karyopharm, Servier, Beigene, Nurix Inc, Cellectar, Janssen, SeaGen, Epizyme,
I‐Mab bio, Gilead, Genetech, and has equity ownership in Compliment Corporation.
Supporting information
Table S1 Patient disease characteristics and vaccinations.
Click here for additional data file.