Study of efficacy and longevity of immune response to third and fourth doses of COVID-19 vaccines in patients with cancer: A single arm clinical trial
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Curated by eLife
eLife assessment
This important study evaluates the immunogenicity of 3rd and 4th doses of SARS-CoV2 vaccinations in patients with cancer. Their study is notable in that neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose. With the definitions and patient population better described, this paper would be of interest to those studying the effects of repeated COVID boosters on Omicron immunity.
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Abstract
Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. Many healthcare regulatory agencies recommend administering ‘booster’ doses of COVID-19 vaccines beyond the standard two-dose series, for this group of patients. Therefore, studying the efficacy of these additional vaccine doses against SARS-CoV-2 and variants of concern is of utmost importance in this immunocompromised patient population
Methods:
We conducted a prospective single arm clinical trial enrolling patients with cancer that had received two doses of mRNA or one dose of AD26.CoV2.S vaccine and administered a third dose of mRNA vaccine. We further enrolled patients that had no or low responses to three mRNA COVID vaccines and assessed the efficacy of a fourth dose of mRNA vaccine. Efficacy was assessed by changes in anti-spike antibody, T-cell activity, and neutralization activity, which were again assessed at baseline and 4 weeks.
Results:
We demonstrate that a third dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination series. The immune response is durable as assessed by anti-SARS-CoV-2 (anti-S) antibody titers, T-cell activity, and neutralization activity against wild-type (WT) SARS-CoV2 and BA1.1.529 at 6 months of follow-up. A subset of severely immunocompromised hematologic malignancy patients that were unable to mount an adequate immune response (titer <1000 AU/mL) after the third dose and were treated with a fourth dose in a prospective clinical trial which led to adequate immune boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant.
Conclusions:
These results indicate that third dose of COVID vaccine induces durable immunity in cancer patients and an additional dose can further stimulate immunity in a subset of patients with inadequate response.
Funding:
Leukemia Lymphoma Society, National Cancer Institute.
Clinical trial number:
NCT05016622 .
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Author Response
Reviewer #1 (Public Review):
Thakkar et al describe the immune effects of 3rd and 4th doses of COVID-19 monovalent vaccines in a diverse cohort of immunocompromised cancer patients. They describe augmentation of anti-Spike antibodies after dose 3, especially seroconversion in 57% of patients, followed by a durable response over six months. The fourth dose was associated with increased anti-Spike antibodies in 67% of patients. T-cell responses were seen in 74% and 94% of patients after the third and fourth doses respectively. Strikingly, neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose.
Strengths:
Diverse cohort (34% Caucasian, 31% AA, 25% Hispanic 8% Asian) including 106 cancer patients after dose 3, of which 47 patients were longitudinally …
Author Response
Reviewer #1 (Public Review):
Thakkar et al describe the immune effects of 3rd and 4th doses of COVID-19 monovalent vaccines in a diverse cohort of immunocompromised cancer patients. They describe augmentation of anti-Spike antibodies after dose 3, especially seroconversion in 57% of patients, followed by a durable response over six months. The fourth dose was associated with increased anti-Spike antibodies in 67% of patients. T-cell responses were seen in 74% and 94% of patients after the third and fourth doses respectively. Strikingly, neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose.
Strengths:
Diverse cohort (34% Caucasian, 31% AA, 25% Hispanic 8% Asian) including 106 cancer patients after dose 3, of which 47 patients were longitudinally assessed for six months, as well as eighteen patients assessed after the fourth dose. Seronegative as well as seropositive patients benefit from a third dose of vaccination. Assessment of cellular (T cell) immune responses and viral neutralization against wild-type as well as Omicron variant is commendable.
Weaknesses:
The efficacy of the bivalent vaccine (Omicron specific) is not studied here, since the fourth dose of vaccine was a monovalent vaccine. This should be clarified in the discussion.
We have added text in the discussion section regarding this comment, lines 470-472
“The bivalent COVID-19 vaccine was introduced after the enrollment for our study was closed however it is reassuring to see that the bivalent vaccine has better neutralization activity against Omicron sub-variants”
The authors describe an increase in anti-S titers after monoclonal antibodies. Were any of the patients receiving IVIG, and what was the effect, if any on Anti-S antibodies? Characteristics of breakthrough infections, particularly if they had prolonged duration, would be important to include.
We have added text in the results section for IVIG (lines 382-383) and characteristics of breakthrough infections (lines 341-344)
“No patients were on intravenous immunoglobulin (IVIG) at the time of study participation” “Of the 4 breakthrough infections, 1 patient had no symptoms, and 3 had mild symptoms”
Reviewer #2 (Public Review):
In this manuscript, Thakkar and colleagues evaluate the immunogenicity of 3rd and 4th doses of SARS-CoV2 vaccinations in patients with cancer. The authors find that additional vaccine doses are able to seroconvert a subset of patients and that antibody levels correlate with T-cell responses and viral neutralization.
The main strengths of this manuscript are:
- The authors systemically performed a broad array of immunological assessments, including assessments of antibody levels, T cell activity, and neutralization assays, in a large cohort of patients with cancer receiving 3rd and 4th doses of COVID vaccines.
- The authors recruited an ethnically diverse cohort of patients with diverse cancer types, though enrolled participants were enriched for hematological malignancies.
- Prior to FDA/CDC guidance supporting a 4th vaccine dose, the authors recruited participants with no or inadequate responses into a prospective clinical trial of a 4th dose, the results of which are outlined here.
- The authors' findings that patients with hematologic malignancies and those receiving anti-CD20/BTK inhibitors have lower immunological responses to SARS-CoV-2 vaccines are consistent with multiple prior studies, including prior studies from these authors.
- The authors also find that 3rd and 4th COVID vaccine doses are able to seroconvert a subset of patients with no or "inadequate" responses, though it's unclear whether seroconversion is enough for true protection from SARS-CoV-2 infection.
The main weaknesses of the manuscript include:
- The study cohorts disproportionately enrolled patients with hematological malignancies who have been previously shown to mount lower immunological responses to COVID-19 vaccines; thus, the findings may not be representative of a typical oncology patient population.
We have clarified this in the discussion (lines 465-466)
“However, caution should be exercised in generalizing these results to the broader immunosuppressed population given the small sample size of our cohort and the disproportionately high representation of hematologic malignancy patients”
- The subgroup analyses were relatively small.
The discussion text in line 464-465 is in concordance with this observation
“However, caution should be exercised in generalizing these results to the broader immunosuppressed population given the small sample size of our cohort and the disproportionately high representation of hematologic malignancy patients”
- The nomenclature used in the manuscript was confusing when it came to "baseline" assessments and boosters versus additional doses of vaccines.
We have clarified the nomenclature throughout the manuscript
- Ultimately, the major limitation of this manuscript is that antibody levels/T-cell responses/neutralization are surrogates for immune protection against SARS-CoV-2, but it's unclear what defines the ideal cutoffs for protection. Simply seroconverting may still be insufficient. The authors don't provide data showing antibody levels as relates to breakthrough infection, likely because they are underpowered for this analysis.
We have added text to expand on this further lines 475-482
“Further efforts are also needed to better determine cut-off values at which anti-S antibody levels provide protection from symptomatic COVID-19. At the present time, this data exists only for neutralizing antibody titers[36, 44] and the commercially available anti-S antibody assays are quite heterogenous with efforts being made to improve equivalency in titer reporting[45]. Our study while providing a correlation between anti-S antibody titer and neutralizing antibody titer supports that the higher the titer, the better neutralization is expected and by extrapolation, less likelihood of symptomatic infection however this needs to be confirmed in larger, systematic studies”.
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eLife assessment
This important study evaluates the immunogenicity of 3rd and 4th doses of SARS-CoV2 vaccinations in patients with cancer. Their study is notable in that neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose. With the definitions and patient population better described, this paper would be of interest to those studying the effects of repeated COVID boosters on Omicron immunity.
-
Reviewer #1 (Public Review):
Thakkar et al describe the immune effects of 3rd and 4th doses of COVID-19 monovalent vaccines in a diverse cohort of immunocompromised cancer patients. They describe augmentation of anti-Spike antibodies after dose 3, especially seroconversion in 57% of patients, followed by a durable response over six months. The fourth dose was associated with increased anti-Spike antibodies in 67% of patients. T-cell responses were seen in 74% and 94% of patients after the third and fourth doses respectively. Strikingly, neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose.
Strengths:
Diverse cohort (34% Caucasian, 31% AA, 25% Hispanic 8% Asian) including 106 cancer patients after dose 3, of which 47 patients were longitudinally assessed for six months, as …Reviewer #1 (Public Review):
Thakkar et al describe the immune effects of 3rd and 4th doses of COVID-19 monovalent vaccines in a diverse cohort of immunocompromised cancer patients. They describe augmentation of anti-Spike antibodies after dose 3, especially seroconversion in 57% of patients, followed by a durable response over six months. The fourth dose was associated with increased anti-Spike antibodies in 67% of patients. T-cell responses were seen in 74% and 94% of patients after the third and fourth doses respectively. Strikingly, neutralization of Omicron was absent in all patients after the third dose but increased to 33% after the fourth dose.
Strengths:
Diverse cohort (34% Caucasian, 31% AA, 25% Hispanic 8% Asian) including 106 cancer patients after dose 3, of which 47 patients were longitudinally assessed for six months, as well as eighteen patients assessed after the fourth dose.
Seronegative as well as seropositive patients benefit from a third dose of vaccination.
Assessment of cellular (T cell) immune responses and viral neutralization against wild-type as well as Omicron variant is commendable.Weaknesses:
The efficacy of the bivalent vaccine (Omicron specific) is not studied here, since the fourth dose of vaccine was a monovalent vaccine. This should be clarified in the discussion.
The authors describe an increase in anti-S titers after monoclonal antibodies. Were any of the patients receiving IVIG, and what was the effect, if any on Anti-S antibodies?
Characteristics of breakthrough infections, particularly if they had prolonged duration, would be important to include. -
Reviewer #2 (Public Review):
In this manuscript, Thakkar and colleagues evaluate the immunogenicity of 3rd and 4th doses of SARS-CoV2 vaccinations in patients with cancer. The authors find that additional vaccine doses are able to seroconvert a subset of patients and that antibody levels correlate with T-cell responses and viral neutralization.
The main strengths of this manuscript are:
- The authors systemically performed a broad array of immunological assessments, including assessments of antibody levels, T cell activity, and neutralization assays, in a large cohort of patients with cancer receiving 3rd and 4th doses of COVID vaccines.
- The authors recruited an ethnically diverse cohort of patients with diverse cancer types, though enrolled participants were enriched for hematological malignancies.
- Prior to FDA/CDC guidance supporting a …
Reviewer #2 (Public Review):
In this manuscript, Thakkar and colleagues evaluate the immunogenicity of 3rd and 4th doses of SARS-CoV2 vaccinations in patients with cancer. The authors find that additional vaccine doses are able to seroconvert a subset of patients and that antibody levels correlate with T-cell responses and viral neutralization.
The main strengths of this manuscript are:
- The authors systemically performed a broad array of immunological assessments, including assessments of antibody levels, T cell activity, and neutralization assays, in a large cohort of patients with cancer receiving 3rd and 4th doses of COVID vaccines.
- The authors recruited an ethnically diverse cohort of patients with diverse cancer types, though enrolled participants were enriched for hematological malignancies.
- Prior to FDA/CDC guidance supporting a 4th vaccine dose, the authors recruited participants with no or inadequate responses into a prospective clinical trial of a 4th dose, the results of which are outlined here.
- The authors' findings that patients with hematologic malignancies and those receiving anti-CD20/BTK inhibitors have lower immunological responses to SARS-CoV-2 vaccines are consistent with multiple prior studies, including prior studies from these authors.
- The authors also find that 3rd and 4th COVID vaccine doses are able to seroconvert a subset of patients with no or "inadequate" responses, though it's unclear whether seroconversion is enough for true protection from SARS-CoV-2 infection.
The main weaknesses of the manuscript include:
- The study cohorts disproportionately enrolled patients with hematological malignancies who have been previously shown to mount lower immunological responses to COVID-19 vaccines; thus, the findings may not be representative of a typical oncology patient population.
- The subgroup analyses were relatively small.
- The nomenclature used in the manuscript was confusing when it came to "baseline" assessments and boosters versus additional doses of vaccines.
- Ultimately, the major limitation of this manuscript is that antibody levels/T-cell responses/neutralization are surrogates for immune protection against SARS-CoV-2, but it's unclear what defines the ideal cutoffs for protection. Simply seroconverting may still be insufficient. The authors don't provide data showing antibody levels as relates to breakthrough infection, likely because they are underpowered for this analysis.
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