Study of efficacy and longevity of immune response to 3rd and 4th doses of COVID-19 vaccines in patients with cancer: a single arm clinical trial
- Albert Einstein College of Medicine, United States
- Icahn School of Medicine at Mount Sinai, United States
- Montefiore Medical Center, United States
- Euroimmun, United States
Abstract
Background: 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 2-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 3rd 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 4th dose of mRNA vaccine. Efficacy was assessed by changes in anti-spike antibody, T-cell activity and neutralization activity were again assessed at baseline and 4 weeks.
Results: We demonstrate that a 3rd 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-S antibody titers, T-cell activity and neutralization activity against wild-type 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 3rd dose and were treated with a 4th 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 3rd 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 identifier: NCT05016622.
Data availability
The data for this clinical trial contains protected health information for the participants that includes a large amount of information as to specific dates/treatments/cancer diagnoses. Therefore, it is prudent to protect this information and it does not seem appropriate to put the information out in the public domain. For example- patients' specific cancer diagnoses, treatment received, COVID-19 vaccine dates can be viewed as sensitive information in the aggregate. If we remove this detailed information from the dataset then the dataset would end up being very limited and not useful for any researcher. Therefore, we believe that making the dataset available through the corresponding author based on individual well-supported requests will allow researchers access to complete data while protecting potentially identifiable patient-level information from the public domain. We are more than happy to share the deidentified database with the reviewers/editors (for review purposes only). If an interested researcher wishes to acquire the data, the aforementioned de-identified dataset can be made available by contacting the corresponding author of the study. While there are no restrictions on data usage per se, we request that future research be done in accordance with standardized guidelines and with local ethics approval. The code is already deposited in GitHubCode availability statement : Computer code has been deposited in GitHub and can be found at https://github.com/kith-pradhan/CovidBooster and https://github.com/kith-pradhan/CovidBooster4th
Article and author information
Author details
Funding
National Cancer Institute (3P30CA013330-49S3)
- Balazs Halmos
NCI Community Oncology outreach program (2UG1CA189859-06)
- Balazs Halmos
leukemia lymphoma society
- Amit K Verma
Centers of Excellence for Influenza Research and Surveillance (HHSN272201400008C)
- Florian Krammer
Centers of Excellence for Influenza Research and Response (75N93021C00014)
- Florian Krammer
Collaborative Influenza Vaccine Innovation Centers (75N93019C00051)
- Florian Krammer
National Cancer Institute (75N91019D00024)
- Florian Krammer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Ethics statement:The study was approved by Montefiore-Einstein institutional review board (IRB# 2021-13204). Participants were recruited after referral to the study from their treating oncologists. At the consent visit, patients were provided with a study overview including initial lab draw, vaccine appointment and follow-up at pre-specified time points. The informed consent document included consent for research samples and consent to protect confidential patient information by the personnel approved under the IRB. Any person not involved with the research study did not have access to patient identifying data. De-identified data was allowed to be shared with collaborators and findings from the study be published. The informed consent document also included consent for a future research lab draw should an improved test for SARS-CoV-2 immunity became available. Finally, the consent included patient's right to withdraw from the study at any time. The patient was provided with a copy of the signed informed consent.
Copyright
© 2023, Thakkar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Study of efficacy and longevity of immune response to 3rd and 4th doses of COVID-19 vaccines in patients with cancer: a single arm clinical trial
eLife 12:e83694.
https://doi.org/10.7554/eLife.83694
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Background:
Clonal hematopoiesis of indeterminate potential (CHIP) was initially linked to a twofold increase in atherothrombotic events. However, recent investigations have revealed a more nuanced picture, suggesting that CHIP may confer only a modest rise in myocardial infarction (MI) risk. This observed lower risk might be influenced by yet unidentified factors that modulate the pathological effects of CHIP. Mosaic loss of the Y chromosome (mLOY), a common marker of clonal hematopoiesis in men, has emerged as a potential candidate for modulating cardiovascular risk associated with CHIP. In this study, we aimed to ascertain the risk linked to each somatic mutation or mLOY and explore whether mLOY could exert an influence on the cardiovascular risk associated with CHIP.
Methods:
We conducted an examination for the presence of CHIP and mLOY using targeted high-throughput sequencing and digital PCR in a cohort of 446 individuals. Among them, 149 patients from the CHAth study had experienced a first MI at the time of inclusion (MI(+) subjects), while 297 individuals from the Three-City cohort had no history of cardiovascular events (CVE) at the time of inclusion (MI(-) subjects). All subjects underwent thorough cardiovascular phenotyping, including a direct assessment of atherosclerotic burden. Our investigation aimed to determine whether mLOY could modulate inflammation, atherosclerosis burden, and atherothrombotic risk associated with CHIP.
Results:
CHIP and mLOY were detected with a substantial prevalence (45.1% and 37.7%, respectively), and their occurrence was similar between MI(+) and MI(-) subjects. Notably, nearly 40% of CHIP(+) male subjects also exhibited mLOY. Interestingly, neither CHIP nor mLOY independently resulted in significant increases in plasma hs-CRP levels, atherosclerotic burden, or MI incidence. Moreover, mLOY did not amplify or diminish inflammation, atherosclerosis, or MI incidence among CHIP(+) male subjects. Conversely, in MI(-) male subjects, CHIP heightened the risk of MI over a 5 y period, particularly in those lacking mLOY.
Conclusions:
Our study highlights the high prevalence of CHIP and mLOY in elderly individuals. Importantly, our results demonstrate that neither CHIP nor mLOY in isolation substantially contributes to inflammation, atherosclerosis, or MI incidence. Furthermore, we find that mLOY does not exert a significant influence on the modulation of inflammation, atherosclerosis burden, or atherothrombotic risk associated with CHIP. However, CHIP may accelerate the occurrence of MI, especially when unaccompanied by mLOY. These findings underscore the complexity of the interplay between CHIP, mLOY, and cardiovascular risk, suggesting that large-scale studies with thousands more patients may be necessary to elucidate subtle correlations.
Funding:
This study was supported by the Fondation Cœur & Recherche (the Société Française de Cardiologie), the Fédération Française de Cardiologie, ERA-CVD (« CHEMICAL » consortium, JTC 2019) and the Fondation Université de Bordeaux. The laboratory of Hematology of the University Hospital of Bordeaux benefitted of a convention with the Nouvelle Aquitaine Region (2018-1R30113-8473520) for the acquisition of the Nextseq 550Dx sequencer used in this study.
Clinical trial number:
