We conducted a cross-sectional study using an anonymous online questionnaire from 34 provincial administrative regions in China between 16 November 2022 and 5 December 2022. During this period, booster doses of COVID-19 vaccines were available to the adult population that had received the basic two doses of COVID-19 vaccines over 6 months. The secondary booster dose of COVID-19 was also recommended for the susceptible population.

Individuals were recruited as participants if they were: (1) able to read and complete the online self-administered questionnaire independently; (2) informed consent to participate in the study. In addition, participants who had incorrect quality control question answers were excluded. The participants' recruitment relied on convenience sampling by disseminating the study questionnaire's URL link or quick response (QR) code on WeChat (https://weixin.qq.com/), which is currently regarded as the most popular instant messaging platform in China.

The sample size was calculated using PASS 21.0.3 (https://www.ncss.com/). A sample size of 789 was produced by a two-sided 95% confidence interval (CI) with a width equal to 0.04, and the proportion of participants with a hesitancy to receive a COVID-19 booster vaccine was estimated as 0.084 according to a recent study (17–19). The formula is as follows:

N is the sample size. Z is the Z-score corresponding to the desired level of confidence. For a two-sided 95% CI, the Z-score is ~1.96. α = 0.05. p is the estimated proportion of participants with a characteristic of interest. ε is the width of CI equal to 0.04. When p is unknown, we can set p = 0.5, and N is equal to 2,401.

The questionnaire used in this study consists of four structures (Supplementary material): (1) Basic demographic information and health condition; (2) pandemic experiences and vaccination status; (3) participants' knowledge and attitudes regarding different immunization routes of COVID-19 vaccination; and (4) the modified Vaccine Hesitancy Scale (VHS).

Considering that limited knowledge or misunderstanding about needle-free vaccination might be a barrier for people to access needle-free vaccination (20), we therefore investigated the cognition of these participants toward self-perceived advantages and disadvantages between intramuscular injection and needle-free vaccination. As we know, healthy adult populations who have completed regular immunization are recommended to vaccinate with the orally aerosolized Ad5-nCoV (Convidecia Air), which is the first needle-free COVID-19 vaccine approved for emergency use by the China government in September 2022. Based on recent knowledge (21, 22), incorrect options were intentionally set in our questionnaire with reverse scoring, which are: (1) advantages: “Needle-free vaccines usually last a longer immune response” and “Needle-free vaccines usually have less side effects” (Actually, there were comparable immune duration and side effects between orally aerosolized Ad5-nCoV vaccine and intramuscularly injected Ad5-nCoV vaccine); and (2) disadvantages: “The time for needle-free vaccines to induce immune response is more slower” and “Needle-free vaccines are inconvenient to administer” (Actually, compared with the traditional intramuscularly injected vaccine, the time for this vaccine to induce an immune response is similar, and the administration of needle-free vaccines is more convenient). Participants who self-reported unawareness of needle-free vaccines or got a zero scores were identified as the incorrect understanding group, and the other participants were identified as the correct understanding group.

In this study, we used the Vaccine Hesitancy Scale (VHS), which was developed by the WHO Strategic Advisory Group on Experts (SAGE) Working Group (23), to quantify participants' hesitancy to COVID-19 booster vaccination. The terms in the original VHS were modified by our experienced researchers in order to fit the latest Chinese COVID-19 epidemic situation and vaccine development. The modified scale had 10 items, and each item was asked on a 5-point Likert scale (strongly disagree, disagree, neither agree nor disagree, agree, and strongly agree). Hesitancy to receive a COVID-19 booster vaccine was defined as individuals with 30 scores or less of a total of 50 scores using the hesitancy scale. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) indicated that this scale had good reliability and validity (Supplementary Tables 2, 3), consistent with our previous studies (24–26).

Descriptive analyses were conducted to describe the involved participants. Frequencies and proportions were calculated for categorical variables, and continuous variables were summarized by mean and standard deviation. Bivariate analyses were then undertaken to assess variable associations in the group of respondents who reported a hesitancy to receive a COVID-19 booster vaccine. To determine which factors might be associated with this hesitancy, we then conducted a multivariate logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) with a backward step-wise approach. Factors with a P < 0.2 in the bivariate analyses for hesitancy were included in the logistic regression model. Data were analyzed using R 4.1.3 and SPSS 26.0 (IBM). Statistical significance was set at a P < 0.05.

The protocol for this study was approved by the Ethics Committee of the School of Public Health (Shenzhen), Sun Yat-sen University (approval number: SYSU-PHS-IACUC-2022-065). Participation was voluntary, and informed consent was obtained at the beginning of the questionnaire.

A total of 3,244 (82.9%) of the 3,911 respondents recruited in this survey were considered valid. Participants' mean (±SD) age was 31.81 (±8.88) years, and 91.6% of them were aged between 18 and 44 years old. For the educational level, 66% of the participants had reached a bachelor's degree or even a higher degree. In addition, 151 (4.7%) participants suffered from various chronic diseases (Table 1).

Consistent with the recommended vaccination procedures at the time of our investigation, 3,059 (94.3%) of participants had received the regular two doses of COVID-19 vaccines, and 2,314 (71.3%) of participants had received another booster dose of COVID-19 vaccines.

According to the score of the VHS and its classified criteria, 2,868 (88.4%) of participants were positive for COVID-19 vaccination, while 376 (11.6%) of participants were verified to be in a state of vaccine hesitancy. The further chi-square test showed that participants of different sexes, educational levels, occupations, and monthly incomes had different levels of vaccine hesitancy.

Among different immunization routes of COVID-19 vaccines, 63.2% of participants thought they had a good understanding (fully understood or well-understood) of the immunization route of intramuscular injection. By contrast, there were only 20.7, 9.2, 9.4, and 6.0% of participants had a self-perceived good understanding of inhalation vaccine, nasal spray vaccine, oral vaccine, and microneedle patch vaccine, respectively (Figure 1A). Consistent with the level of understanding toward various immunization routes of vaccination, there was the strongest acceptance for intramuscular injection (76.5%), followed by oral inhalation (64.4%), nasal spray (43.0%), oral capsule (48.2%), and microneedle patch (48.4%; Figure 1B).

We then investigated the participants' cognition about the advantages and disadvantages of traditional intramuscular injection vaccines and burgeoning needle-free vaccines. The majority (43.3%) thought that the main advantage of needle-free immunization was “no injection/no pain,” 24.0% thought that the main advantage was “reduce medical waste,” and 20.5% thought that needle-free immunization could be “self-service and save medical resources.” By contrast, only 13.0% of participants chose the induction of mucosal immunity, and 7.4% chose “More effectively block virus infection.” On the other side, the top three options for disadvantages for participants were “Not sure/I don't know” (29.3%), “Not easy to control the doses” (25.7%), and “Vulnerable to external influences (such as cough and sneeze)” (23.7%). Of note, as for these incorrect options, ~15% of participants chose at least one incorrect answer for each question, implying that these participants had limited knowledge and misunderstandings about needle-free immunization (Figures 2A, B).

Considering that needle-free vaccines are likely to be the most promising immunization routine in future, we specifically investigated people's knowledge about needle-free immunization and the associated factors. In our survey, we found that 47.3% of participants acquired vaccine knowledge from internet websites, 37.0% from popular science propaganda at workplaces or schools, and 25.0% from telecasts (Figure 2C). Of note, 20.6% of participants chose “never heard it,” indicating that this population did care about vaccine-related information. In addition, most participants regarded safety (94.0%) and vaccine efficacy (87.1%) as the main factors when receiving a vaccination, followed by “easy to gain and vaccination” (43.2%), “National recommendations” (31.7%), and “price” (22.5%; Figure 2D).

Further analysis demonstrated that there was a statistical correlation between the participants' vaccine knowledge level and the ways to access vaccine information. Those who obtained vaccine information through websites, newspapers, magazines, telecasts, and professional literature had a higher score than those who obtained it in other unofficial ways or never cared about the vaccine information (Table 2 and Supplementary Table 4). Interestingly, those participants who were only willing to receive an intramuscular vaccine had a lower cognition score (incorrect understanding) than those who were willing to receive a needle-free vaccine. As expected, participants with a higher education level had a higher frequency of acquiring the correct vaccine information.

Previous studies showed that needle phobia (“Afraid of needles”) might be a factor associated with vaccine hesitancy (27–29), and we thus investigated this topic in this study. In our questionnaire, we defined those participants as having “Potential needle-phobia” if they were: (1) not vaccinated due to fear of needles or (2) regarded the pain as the main factor to affect whether receiving vaccination. However, Pearson's chi-square test analysis showed that participants who were considered “potential needle-phobia” had no statistical difference between other participants on the status of vaccine hesitancy, indicating that injection fear may not be a major factor that led to vaccine hesitancy in the Chinese population (Supplementary Table 1).

We further found that these people who had gotten at least one dose of the COVID-19 vaccine, willing to receive an intramuscular injection/inhalation or oral vaccine, were more likely to accept the COVID-19 booster vaccination. Participants who chose “not sure or didn't know about the advantages of needle-free vaccine” were less likely to accept the COVID-19 booster vaccination (Table 3). In addition, these people who had a high education level (graduate student or above) and a high income (15,000 RMB and above/per month) were also less likely to accept the COVID-19 booster vaccination. However, sex, occupation, age, residence place, or chronic disease condition were not significantly correlated with vaccine hesitancy toward COVID-19 booster vaccination (Supplementary Table 5).