What Is the State-of-the-Art in Clinical Trials on Vaccine Hesitancy 2015-2020?

"Studies about vaccine hesitancy seem to be especially relevant due to the need to ensure high vaccination rates to achieve herd immunity during the COVID-2019 pandemic..."

Citizens who are vaccine hesitant show a variable degree of indecision about getting a specific vaccine or about vaccination in general. Vaccine-hesitant individuals are represented by heterogeneous groups and may be influenced by different intrinsic and extrinsic elements (e.g., individual, contextual, and/or group factors). This systematic review examines clinical trials (e.g., randomised and controlled clinical trials) on vaccine hesitancy between 2015-2020. By summarising key findings of these studies, the systematic review aims to make the available evidence more accessible to health professionals, researchers, decision makers, patients, and the public.

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, the researcher screened five databases - PubMed, Cochrane Library, DOAJ, SciELO, and b-on - using the keywords "vaccine hesitancy" and ("randomized controlled trial" or "clinical trial"). The 35 selected studies, which were written in English, Portuguese, French, or Spanish, accounted for at least 2,023 health professionals and 59,467 subjects. Qualitative and quantitative evidence of the selected studies was collected with regard to study objectives, number of participants, methods and results, and conclusions. (See Table 1 in the paper.)

Selected trials were classified into five topics:

• Children/paediatric (n = 5) - Healthcare professionals were identified as the most trustworthy messengers, who should provide balanced information (e.g., risks vs. benefits). Among the communication techniques covered in the studies were storytelling, emotive anecdotes, or other persuasive messaging strategies. Studies indicate that health professionals should:
  • Tailor the information to the intended audience;
  • Understand parents' hesitancy and the specific context (e.g., managing misinformation about vaccination);
  • Present vaccination as the default approach (e.g., early in pregnancy) and communicating both social and individual responsibility;
  • Use technology to promote vaccination; and
  • Improve parents' vaccine literacy and critical thinking skills (e.g., through vaccine education materials).

  However, evidence about the impact of face-to-face information between health professionals and caregivers on children's vaccination status seems to be low to moderate.

• Online or electronic information (n = 5) - The literature indicates that electronic resources, such as apps, websites, internet-based interventions/platforms, games, or social media applications ("apps"), are potentially useful to disseminate correct and intelligible information about vaccination. Examples include:
  • Virtual reality (VR) through a head-mounted display unit promoted participants' understanding of key immunisation concepts and their integration in the story.
  • An expert-moderated vaccine social media space constituted a suitable platform for parents to collect accurate vaccine information, express vaccine concerns, and/or ask questions to vaccine experts.
  • The use of an app produced positive outcomes via provision of vaccine information.
  • An internet-based intervention/platform positively enhanced vaccine-hesitant pregnant women's attitudes on vaccines.
  • During pregnancy, parental vaccine behaviours may be positively influenced by web-based vaccine information with social media apps.

  Besides the lack of representativeness, an increased rate of vaccination after the administration of online or electronic information was not demonstrated in the selected studies. Thus, future studies should be longitudinal and prospective, with the goal of evaluating the impact of providing online information on both subjects' vaccine hesitancy and vaccination rates.

• Vaccination against a specific disease (n = 15) - Sample findings:
  • Human papillomavirus (HPV) - Communication-based interventions between health professionals and parents or adolescents increased adherence to HPV vaccination and/or vaccination intention among adolescents. Communication about HPV vaccination between caregivers and health professionals should be carefully tailored and conducted.
  • Influenza - Tailored communication interventions by health professionals were relevant to promote vaccine uptake and prevent vaccine hesitancy. However, online messages were not sufficiently impactful to change participants' perceptions and attitudes toward flu vaccination and/or to facilitate the dissemination of these messages. Future communication interventions, including the diffusion of online messages, should address the most frequently reported barriers to influenza vaccination, such as subjects' decreased perceived effectiveness of the vaccine, a lack of trust in health authorities, safety concerns, low perceived severity/risk of the disease, lack of recommendations by health workers, or a limited number of interactions with health services.
  • Diphtheria-tetanus-toxoid and pertussis (Tdap) - The number of identified trials about Tdap vaccine hesitancy was scarce. Jarrett al. (2015), a systematic review, reported that: reminder-recall interventions increased DTP3 vaccination (one study from Pakistan); social mobilisation among parents produced a positive effect on DTP1 and DTP3 (evidence varied between moderate to low: one study from Pakistan and one study from Nigeria); communication tool-based training for healthcare workers had a positive effect for DTP3 (one study from Pakistan); and an information-based training for healthcare workers increased DTP3 vaccination (one study from Turkey). Further research about vaccine hesitancy on diphtheria vaccination is recommended.
  • COVID-19 - Additional studies about this particular type of vaccine hesitancy are also recommended, as only one review about COVID-19 vaccination was selected. In this study, collaboration between health professionals and certain less favoured communities (e.g., HIV-positive Black Americans) was recommended for developing and implementing personalised strategies to promote COVID-19 vaccination and treatment uptake.
• Educational strategies (n = 6) - Training of health professionals was found in diverse trials to lead to improvement of knowledge, communication skills, comfort level, and ability to discuss vaccination or vaccine hesitancy. However, information-based training of health professionals may be less effective on vaccine uptake than communication-tool-based training. Parents who received training and/or motivational interviews showed lower vaccine hesitancy and greater intention to vaccinate their children than non-trained parents, though further studies about the impact of tailored communication and training of parents and/or adolescents on vaccine hesitancy are recommended.
• Miscellaneous: Extrinsic factors (n = 4) - Sample findings: Reminder-recall approaches or other communication interventions can positively change the behaviour of vaccine-hesitant parents; compulsory vaccination may contribute to increasing the number of vaccine-hesitant individuals; and a tool to understand, evaluate, and monitor vaccine hesitancy in diverse global settings should be developed (e.g., Likert scales).

The paper outlines study limitations and potential biases of the selected studies (i.e., study findings may not be representative) and also recommends specific future research directions. On the latter issue, the author suggests, for instance, that:

• Research must be strongly theoretically grounded, documented, and reproducible (e.g., ideally, study protocols should be public).
• Tailored research about vaccine hesitancy should be regularly carried out, since the needs of a certain population are potentially variable during a certain period.
• Vaccine hesitancy must be continuously monitored in communities/populations, since the number of hesitant individuals is expected to be variable.
• Contact with citizens who have opted to not get a certain vaccine by health authorities is recommended to understand their motivations and to evaluate possible negative impacts (e.g., SARS-Cov-2 spread). This contact must be strictly designed to respect ethical standards and subjects' individual opinions and rights (e.g., confidentiality of data).

In conclusion: "The number of identified trials, research topics, multicentric and/or longitudinal/prospective studies related to vaccine hesitancy were limited in the last five years (2015-2020)....In general, the conclusions of the present systematic review are aligned with those of Jarret et al. (2015), although studies about targeting multiple audiences (e.g., involvement of religious or traditional leaders, social media, or mass media) were not identified in the present systematic review. These studies were mainly identified in developing countries. According to the findings of the systematic review of Jarrett et al. about vaccine hesitancy (2007 to 2013), dialogue-based approaches through targeting multiple audiences were more likely to produce positive outcomes. Vaccine hesitancy was recognized as a complex issue. The selected studies were classified as highly heterogeneous about their design and outcomes; consequently, it was not possible to define more general study conclusions."