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
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.
Reviewing Editor
- Jameel Iqbal, DaVita Labs, United States
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.
Version history
- Preprint posted: July 6, 2022 (view preprint)
- Received: September 24, 2022
- Accepted: March 5, 2023
- Accepted Manuscript published: March 28, 2023 (version 1)
- Version of Record published: April 25, 2023 (version 2)
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.
Metrics
-
- 1,033
- views
-
- 190
- downloads
-
- 12
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Medicine
The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Slc2a2 (also known as Glut2) knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in the body’s defense mechanisms against a threat – were the top candidates which were either upregulated or downregulated in renal Slc2a2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving the efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria but are met with a compensatory increase in endogenous glucose production.
-
- Developmental Biology
- Medicine
From a forward mutagenetic screen to discover mutations associated with obesity, we identified mutations in the Spag7 gene linked to metabolic dysfunction in mice. Here, we show that SPAG7 KO mice are born smaller and develop obesity and glucose intolerance in adulthood. This obesity does not stem from hyperphagia, but a decrease in energy expenditure. The KO animals also display reduced exercise tolerance and muscle function due to impaired mitochondrial function. Furthermore, SPAG7-deficiency in developing embryos leads to intrauterine growth restriction, brought on by placental insufficiency, likely due to abnormal development of the placental junctional zone. This insufficiency leads to loss of SPAG7-deficient fetuses in utero and reduced birth weights of those that survive. We hypothesize that a ‘thrifty phenotype’ is ingrained in SPAG7 KO animals during development that leads to adult obesity. Collectively, these results indicate that SPAG7 is essential for embryonic development and energy homeostasis later in life.