The COVID-19 pandemic continues to impose burdens of morbidity and mortality while disrupting societies and economies worldwide since 2020. These negative impacts motivated pharmaceutical companies to develop a vaccine immediately. Vaccination of people against COVID-19 has now started in many countries [1]. Governments prepare themselves to ensure large-scale equitable access and distribution of safe and effective COVID-19 vaccines. This will require sufficient health system capacity and effective strategies to increase trust in vaccines and those who deliver them [2]. For decades, vaccines have been a successful measure to eliminate and prevent numerous infections. However, concern about vaccine hesitancy is growing worldwide, prompting the World Health Organization (WHO) to declare it among the top 10 health threats in 2019 [3]. In 2015, the WHO Strategic Advisory Group of Experts on Immunization defined vaccine hesitancy as a “delay in acceptance or refusal of vaccination despite the availability of vaccination services” [4]. In many countries, vaccine hesitancy and misinformation present substantial obstacles to achieving a high coverage rate necessary to attain herd immunity to flatten the epidemic curve [5,6]. Several determinants influence whether an individual refuses, delays, or accepts some vaccines. These include historical, socioeconomic, cultural, ecological, health system/institutional, and political factors [7].

Governments, public health officials, and advocacy groups must be prepared to address the issue of vaccine hesitancy and lower vaccine acceptance rates [2]. Misinformation regarding the benefits, medicinal composition, and adverse effects of vaccination spread through multiple channels could have a considerable effect on the acceptance and increased COVID-19 vaccine hesitancy [8]. Effective interventions should directly address community-specific concerns or misconceptions and be sensitive to religious or cultural beliefs [9]. Trust in government is strongly associated with vaccine acceptance and can contribute to public compliance with recommended actions [10]. Clear and consistent communication by government officials is central in building confidence in vaccine programs among individuals. This includes explaining the development of vaccines, how it works, and its safety and efficacy. Campaigns should also aim to explain a vaccine’s level of effectiveness, the time needed for attaining protection, and the importance of population-wide inoculation with the COVID-19 vaccine to achieve herd immunity. Health communication must reach all communities to enhance vaccine literacy to prevent future infections and mortality [11,12]. Effective and strategic health messages are one of the key approaches in assisting higher authorities to deal with increased vaccine hesitancy and to slow the spread of the infection. Improving vaccine uptake among those most hesitant will be of utmost importance in reaching the immunization rates needed for community immunity [13,14].

Further, some unintended consequences have emerged since the inception of the COVID-19 pandemic, such as lifestyle and behavior changes, impacts on mental health, and economic consequences. These consequences are likely to increase over time as the multiple waves of the COVID-19 pandemic continue to develop [15].

India, being one of the most populated countries in the world, has been struggling to attain the goal of 90% vaccine coverage under the national immunization schedule due to several reasons including vaccine hesitancy [16,17]. According to the National Family Health Survey (NFHS) 1 (1992-1993), there was 65% vaccine coverage, which increased to 82% in NFHS 2 (1998-1999). This was followed by 81% as per NFHS 3 (2005-2006) to a substantial decline to 69.7% as per the NFHS 4 (2015-16) in Tamil Nadu [18]. In the region of Chennai, Tamil Nadu, a southern state in India, a considerable decline in the vaccine coverage rate has been observed over the past 20 years [19,20].

The government of India has now opened up COVID-19 vaccinations for everyone 18 years and older. Until May 8, 2021, 169,439,663 total doses were administered, out of which 133,980,544 received the first dose and 35,459,119 were administered the second dose. Meanwhile, in Tamil Nadu to date, 6,480,287 have been vaccinated, of which 4,835,514 received the first dose and 1,644,773 received the second dose. As of May 8, 2021, Tamil Nadu stands 10th in India in administering total vaccine doses. Tamil Nadu recorded a decline in the vaccination rate between April 1 to 10, 2021, compared to March 22 to 29, 2021. The vaccination coverage once again recorded a dip on April 18, 2021. On April 18, 41,120 were newly vaccinated as compared to 138,298 the previous day. Even though the new cases in Tamil Nadu are rising and the vaccinations are open for individuals 18 years and older, the new vaccinated rate is low and inconsistent [21]. This reduction and inconsistency in the vaccine coverage rates could be due to vaccine hesitancy among individuals. There also seems to be a paucity of data on the rate of COVID-19 vaccine acceptance, vaccine hesitancy, and factors contributing to them. To control vaccine preventable diseases, it is imperative to identify the key challenges and opportunities to reduce vaccine hesitancy and recoup vaccine confidence among individuals. Hence, this study aims to examine the factors that influence vaccine hesitancy and vaccine acceptance, and to explore the unintended consequences of COVID-19 infections. The study will further explore the association between sociodemographic characteristics; health status; COVID-19–related knowledge, attitude, and practices; and its influence on vaccine hesitancy and acceptance among individuals living in urban and rural settings of Chennai District of Tamil Nadu, a southern state in India.

This study aims to assess the rates of vaccine acceptance and vaccine hesitancy among the adult population of Chennai, Tamil Nadu; to investigate the determinants of vaccine acceptance and vaccine hesitancy; to explore the unintended consequences of COVID-19 infection; and to formulate an evidence-driven intervention model to facilitate uptake of the COVID-19 vaccine in Chennai and other states of India.

A cross-sectional study will be conducted between the period of January 2021 and January 2023. The study participants will be recruited from 11 selected urban and rural settings of Chennai District of Tamil Nadu, a southern state in India. A total of 11 primary health centers (PHCs) of Chennai District were selected for the study, namely, Thiruninrarvur, Thirumazhisai, Kathavur and Pallavedu, Veppampattu, Mittinamallee, Vilinjiyambakkam, Periyar Nagar, Parithipattu, Papparambakkam, Ulundai, and Poonamallee. It was made sure that all the selected PHCs are comparable with regard to available resources and living conditions. This ensured that these PHCs are not systematically different from each other and are representative of all the PHCs in Chennai.

The study plans to recruit a total of 25,000 individuals using a nonprobability complete enumeration sampling method. The selected sampling method would allow the researchers to study more than one aspect of all items of the population and obtain data from each and every unit of population. Each item will be observed personally by the researchers. The collected data will be reliable, accurate, and truly representative of the whole population. In addition, the data obtained using the complete enumeration method can be used as a basis for future studies [22]. The eligible study participants will comprise the following: individuals 18 years and older, individuals residing in the selected urban and rural settings, and individuals consenting to participate in the study. Individuals having any mental or physical challenges that might affect their ability to participate in the study will be excluded from the study.

The institutional review board–approved informed consent form will be administered by the research team to the eligible individuals for the study. The research team will describe the study, time required, and benefits of the study results to the participants, and those willing to participate and give their consent will be enrolled in the study. The participants should be able to read and understand the questionnaire. In case any participant is illiterate, ethical consent will be obtained with the help of a legally acceptable representative or an impartial witness [23]. In addition, the illiterate participants will be explained the questionnaire in the local Indian dialects to aid in the usefulness and generalizability of the study. Data gathered will be stored in a secure manner ensuring data privacy and confidentiality. Written informed consent will be obtained in both English and local Indian dialects. Study participants will be allowed to withdraw from the study at any time mentioning the reasons for withdrawal. All data including those from study withdrawals will be reported in the final analysis. No monetary compensation will be given, and those agreeing to participate will be offered snack meals. Every individual’s time will be respected, and their voluntary participation will be appreciated. Nonmonetary forms of compensation would help to avoid coercion and undue inducement that might impact the results of the study [24].

Data collection and data entry will be performed by a team of data collectors and data management personnel. The data will be collected at a one-time point by administering the study questionnaire to the eligible study participants (Multimedia Appendix 1). For designing and standardizing the questionnaire, the researchers performed a pilot study involving a sample of 2500 individuals. Initial data will be gathered on paper and then entered into the computer using Microsoft Excel (Microsoft Corporation). For the main survey, the data will be recorded electronically using computer-based software. To ensure efficiency and high-quality data collection and processing, the following data management protocol is in place: a clearly defined study manual, a well-trained team of data collectors, weekly meetings with the research team, weekly data checks, maintenance of study participant contact, and maintenance of study participant data instrument logs.

Data security will be ensured through regular backups, password-protected computers, and data files stored in a locked file cabinet in an office. The information will be accessible to members of the research team only. Data will be stored in a password-protected computer in a locked office of the principal investigator for 3 years from the point of study completion at which time they will be destroyed.

The study outcomes include factors associated with COVID-19 vaccine acceptance and hesitancy, and knowledge, attitude, and practices related to COVID-19 and vaccination. The authors of the study will also explore the factors affecting unintended consequences of COVID-19 infection across urban and rural settings in an Indian setting.

The gathered data will be presented in tables comprising the recorded characteristics of all variables. These tables will serve the purpose of data quality control to find out inconsistencies in the data patterns and outliers or any missing data. Descriptive analysis will be conducted to report the means and SDs of the continuous variables and frequency analysis of the categorical variables. T tests will be performed to compare the means between the continuous variables and a categorical dependent variable, while chi-square analysis will be performed for the categorical variables. Multivariate regression analysis will be performed to determine the predictors of the outcome variables of vaccine acceptance and hesitancy. All analysis will be performed using SAS v9.1 and reporting of the results will be done at 95% CIs and P=.049.

A detailed research plan and scheduled timeline of the tasks involved in the study are presented in Table 1.

The study bearing protocol number PMCHRI-IHEC-029 gained approval from the Panimalar Medical College Hospital and Research Institute Institutional Human Ethics Committee (Central Drugs Standard Control Organization Registration No. ECR/1399/Inst/TN/2020) in January 2021 with approval No. PMCH&RI/IHEC/2021/037 dated January 13, 2021. The study will be conducted according to the Declaration of Helsinki, as it involves human participants [27].

Findings of the study will be disseminated through peer-reviewed publications and national and international conference presentations. Findings will also be disseminated to the local community health leaders and other state officials and policy makers for data-driven, evidence-based informed decision making.