Safety of COVID-19 vaccines in patients with non-communicable diseases: a protocol for systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: The COVID-19 global pandemic has posed enormous threats to public health around the world. Vaccines are considered the best therapeutic strategy against the COVID-19 pandemic. However, the adverse reactions of vaccines significantly affect the rates of vaccination and may be more serious in patients with non-communicable diseases (NCDs). This protocol aims to conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) which analysed the safety of vaccines in patients with NCDs. METHODS AND ANALYSIS: This study will be according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. A comprehensive search will be carried out to identify registered RCTs in PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Library between 1 January 2020 and 31 May 2022. Selection of trials, data extraction, risk of bias assessment and quality of evidence assessment will be done by two researchers, and disagreements will be resolved by the corresponding author. The primary outcomes are local and systemic adverse events of vaccines in patients with NCDs. Additional outcomes are related events caused by vaccine adverse events, including but not limited to cases of adverse events leading to discontinuation from a dose or withdrawal from participation in the trial. Heterogeneity will be assessed with I2 statistics and data analysis will be conducted with RevMan V.5.4.1. ETHICS AND DISSEMINATION: This is a protocol and ethical approval is not necessary. The results of this protocol will be disseminated to peer-reviewed publications or conference presentations. PROSPERO REGISTRATION NUMBER: CRD42021254914. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

This protocol follows the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols.

This study will systematically report the safety of COVID-19 vaccines in patients with non-communicable diseases and the quality of evidence will be assessed with the Grading of Recommendations, Assessment, Development and Evaluation methodology.

The types of vaccines could be a potential source of heterogeneity between the included trials.

Introduction

The COVID-19 pandemic, caused by SARS-CoV-2, has spread to more than 220 countries and areas.1 2 People of all ages are susceptible to SARS-CoV-2 infection according to known evidence, and the median age of infected patients is around 50 years.3 Fever, cough and fatigue are common symptoms of mild COVID-19 cases, and dyspnoea, bilateral lung infiltration and haemodynamic instability for severe cases.3–5 On 10 January 2022, the WHO reported more than 300 million confirmed cases of COVID-19 around the world, including more than 5 million deaths.6 Although targeting the virus and respiratory support treatment have reduced mortality rates among patients with COVID-19, it is widely recognised that developing a safe and effective vaccine strategy is crucial to controlling the COVID-19 pandemic.7 8

Currently, there are more than 330 vaccine candidates in development against SARS-CoV-2 and about 137 vaccine candidates in clinical development according to the WHO.9 However, it remains unclear which vaccine strategies will be most successful in combating the COVID-19 pandemic.8 These vaccines in the clinical phase can be divided into six major types: inactivated vaccines, live attenuated vaccines, protein-based vaccines, viral vector vaccines, DNA vaccines and RNA vaccines.10 Based on the platforms and targets, each type of vaccine has its advantages and disadvantages.11 During the severe epidemic situation, numerous COVID-19 vaccines were approved for emergency vaccination even if all phases of clinical trials have not been completed. According to the WHO, as of 8 January 2022, more than 9.1 billion doses of vaccines had been administered.6 However, not only vaccination rates and effectiveness, but also the safety of COVID-19 vaccines should be of high concern.12 Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, respiratory diseases and other chronic diseases, are the leading cause of death and ill health.13 Compared with the general population, the safety of COVID-19 vaccines in patients with NCDs is unclear, such as in patients with chronic kidney disease, especially autoimmune-mediated kidney disease, those receiving renal replacement therapy or those receiving immunosuppressive medications, which may affect the effectiveness of the vaccine or induce progression of the kidney disease.14

At present, some clinical trials have reported the results of COVID-19 vaccines and have systematically reviewed their safety and efficacy,15 16 but to the authors’ knowledge there is no systematic review and meta-analysis of randomised controlled trials (RCTs) reporting on the safety of COVID-19 vaccines in patients with NCDs. Therefore, this study aims to determine the safety of vaccines in patients with NCDs and analyse the influencing factors, including the type of vaccine, severity of COVID-19, and age and gender of patients.

Methods

Study registration

The protocol for this systematic review has been registered with PROSPERO (CRD42021254914; https://www.crd.york.ac.uk/prospero/).

Inclusion criteria

Type of studies

Only RCTs will be included. Observational studies, protocols, meta-analyses, reviews, case reports and animal experiments will be excluded.

Type of participants

Participants are of any gender, race, religion or NCDs. Participants with known SARS-CoV-2 infection, are febrile 24 hours prior to screening, are pregnant or are breast feeding will be excluded.

Type of interventions

The intervention group will be treated with vaccines.

Comparator

The control group will be treated with a placebo.

Type of outcomes

The primary outcomes are local and systemic adverse events of vaccines in patients with NCDs. Additional outcomes are related events caused by vaccine safety, including but not limited to cases of COVID-19, cases of severe COVID-19, vaccine-enhanced disease and cases of adverse events leading to discontinuation from a dose or withdrawal from participation in the trial.

Definition of NCDs according to the WHO

NCDs, also known as chronic diseases, are the result of a combination of genetic, physiological, environmental and behavioural factors and tend to be of long duration (>3 months).

Systematic search and selection of studies

Trials will be identified from electronic databases: PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Library. Search terms include ‘COVID-19 Vaccine’, ‘SARS CoV 2 Vaccine’, ‘SARS 2 Vaccine’, ‘Coronavirus Disease 2019 Vaccine’, ‘2019 Novel Coronavirus Vaccine’, ‘2019 nCoV Vaccine’ and ‘2019 nCoV Vaccine’. Search strategies will be chosen for different databases; the PubMed strategy is shown in online supplemental table 1. The search will be performed in September 2021.

Search results from the electronic databases will be merged using EndNote V.X9 software to remove duplicates. For completed but unpublished clinical trials, the results will be identified by email or other methods of communication with the authors. Two researchers will independently eliminate inconformity literature by scanning titles and abstracts and reading the full text. Disagreements will be resolved by the corresponding author. The selection process is presented in figure 1.

Figure 1

Flow diagram of the study selection.

Updates on the systematic search

Ensuring the accuracy of clinical trials and electronic databases, we will update the search results every month with the same methodology.

Risk of bias assessment

The risk of bias of RCTs will be assessed by Cochrane Collaboration’s risk of bias assessment tool. The tool includes seven questions of bias, each assessed as low risk, unclear risk or high risk. Risk of bias includes random methods, concealment of allocation, blinding (participants, personnel and outcome), incomplete outcome data, selective reporting and others. Two researchers will independently assess the risk of bias of RCTs and any disagreements will be determined by the corresponding author.

Data extraction

The following data from the included studies will be independently extracted by two researchers: (1) general information of studies (lead author, year of publication, country of origin, sample size); (2) participant characteristics (age, gender, NCDs); (3) intervention details (types of vaccines, dosage, vaccination methods, observation period); and (4) relevant outcomes. Any disagreements will be determined by the corresponding author.

Statistical analysis

Synthesis and analysis of data will be conducted with RevMan V.5.4.1 and p<0.05 will be considered significant. Dichotomous variables will be calculated by relative risk with 95% CI and continuous variables will be calculated by weighted mean difference with 95% CI. If necessary, subgroup analysis or sensibility analysis will be performed to detect the resource of between-study heterogeneity. I2 >50% or p<0.1 indicates significant between-study heterogeneity and the results will be calculated using random effects meta-analysis. Potential risk of publication bias will be evaluated with funnel plots.

Quality of evidence assessment

The quality of evidence will be assessed by two independent researchers according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. The results will be assessed as very low, low, moderate or high quality. Any disagreements will be determined by the corresponding author.

Patient and public involvement

No patients were involved.

Ethics and dissemination

This is a protocol using aggregated published data and ethical approval is not required. The results from this protocol will be disseminated to peer-reviewed publications or conference presentations.

Discussion

Popularising vaccination is an important method to eliminate the COVID-19 epidemic, and the safety of vaccines is a key factor in improving the rate of vaccination. However, many people refuse to be vaccinated due to the unknown adverse events of COVID-19 vaccines. Moreover, the safety and efficacy of COVID-19 vaccines have not been ensured in patients with NCDs, such as in patients with immunodeficiency disease or those treated with immunosuppressants. Therefore, timely reporting of adverse events after vaccine administration can help control the COVID-19 pandemic. This systematic review and meta-analysis will assess the safety of COVID-19 vaccines in patients with NCDs, from RCTs, and may provide evidence for vaccination in various populations.