Analysis of COVID-19 clinical trials: A guide to reducing vaccine hesitancy

The US Food and Drug Administration (FDA) has approved emergency use authorization (EUA) of 3 coronavirus disease 2019 (COVID-19) vaccines to fight the severe acute respiratory coronavirus 2 (SARS CoV-2) pandemic in the United States.^1,2,3,4 The Pfizer and Moderna vaccines were approved for a 2 dose series.^1,2 On February 27, 2021, the FDA approved EUA for the Johnson & Johnson® single-dose vaccine sponsored by Janssen Biotech, Inc® also to prevent moderate and severe illness and death from COVID-19 caused by SARS-CoV-2.³

Vaccine hesitancy, unfortunately, remains at the forefront of these vaccines, despite the severe morbidity and mortality caused by COVID-19 and the crippling of daily life around the world in attempts to battle transmission of SARS-CoV-2. Vaccine hesitant individuals and groups have raised questions about the ‘warp speed’ development of the Pfizer and Moderna COVID-19 vaccines; the vaccine safety and efficacy; and whether “it is good for me and my family to take the COVID-19 vaccines?” With the FDA EUA for the single dose Johnson & Johnson® vaccine, 1 question being asked is whether the 1 dose is equivalent to the 2 doses of the Pfizer and Moderna vaccines especially by those who were not in the initial priority groups to receive COVID-19 vaccines. Because Pfizer studies included adolescents aged 16 years and older in their studies, the FDA EUA included this age group as eligible to receive the Pfizer vaccine determining that the benefits of receiving the vaccine outweigh the risks.1 Thus, teenagers and their parents will seek the advice of their pediatricians and pediatric nurse practitioners (PNPs), as well as other pediatric health care providers to make an informed decision about vaccinating their adolescents aged 16 years and older and perhaps themselves, as well.

Additionally, because Pfizer and Moderna have started clinical trials in the United States for children aged 6 months to 17 years, parents will be asking for the opinions of pediatricians and PNPs on whether to enroll their children in a trial or to wait for the outcomes of these clinical trials. As the vaccine clinical trials for children are completed, parents will be asking many questions about the vaccines and the opinions of pediatricians and PNPs on whether to vaccinate their younger children. On March 31, 2021, Pfizer reported the results of their clinical trial in children.⁵ Preparing to answer multiple questions from parents and adolescents in advance, based on the scientific evidence from the randomized control trials (RCTs), is key to reducing vaccine hesitancy and vaccine refusal and to the successful return to the new normal lifestyles for infants, children, and adolescents.

Key talking points developed from the authors’ previous review of the RCTs for the Pfizer and Moderna COVID-19 vaccines are presented.⁶ We also compare the 2 dose Pfizer and Moderna vaccines to the 1 dose Johnson & Johnson vaccines. We highlight vaccine messaging supportive of accepting any of the vaccines as a safe and efficacious way for stopping severe to critical COVID-19 disease in infants, children and adolescents. Additionally, we believe that administration of the COVID-19 vaccine to all school-age children as part of safe return to school initiatives is a critical component of a safe school environment for all.

Johnson & Johnson vaccine development

The Johnson & Johnson vaccine is known as Ad26.COV2.S or JNJ-78436725, and is a recombinant vector vaccine that uses human adenovirus type 26 to encode a stabilized variant of the SARS-CoV-2 spike protein.³ The phase 1-2a trial consisted of a low dose and a high dose vaccine which was shown to be immunogenic after either the low or high dose at a dose of 5×10¹⁰ viral particles (low dose) or 1×10¹¹ viral particles (high dose) per milliliter.² Vaccine safety and efficacy for the Johnson & Johnson vaccine in Phase 1-2a trial after 1 dose of the vaccine was considered to be excellent in all populations producing an antibody and T-cell response that continued to improve 28 days after the 1 dose.⁷ Thus, the Phase 3 trial for the Johnson & Johnson vaccine began as a 1 dose vaccine.² The phase 3 RCT consisted of a double blind and placebo controlled trial of a single dose of 5x 1010 viral particles (low dose) with over 40,000 participants aged eighteen years and older.⁸ Currently a longer term trial comparing the 1 dose vaccine regimen to a 2 dose regimen is underway for the Johnson and Johnson vaccine.²

Johnson & Johnson safety profile

Reports from returned diary cards postvaccination were returned by 402 study participants in Cohort 1 (participants aged 18 to 55 years old) and 403 study participants in Cohort 3 (participants aged 65 years old and older) which included both those who received the high and low dose Johnson & Johnson vaccine.² Data analysis showed that the majority of the adverse reactions (labeled as adverse in this study and in the Pfizer and Moderna studies) were pain at the injection site. Other symptoms reported after dose 1 included fatigue, headache, myalgia, nausea, and pyrexia.² All of which were also reported by study participants in the Pfizer and Moderna clinical trials.

Johnson & Johnson vaccine efficacy

Study efficacy was evaluated in the United States, Latin America, and the South African populations who were a part of the phase 3 study.³ One study endpoint was to assess for the prevention of moderate to severe COVID-19 disease in both the intervention group (vaccine) and the control group (placebo) received 28 days post injection. Data analysis showed the following efficacy: United States = 72%; Latin America = 62%; and South Africa = 57%. Across all geographic locations 85% of the vaccine recipients were protected from severe and critical COVID-19 disease.³ These data support the value of offering the 1 dose Johnson & Johnson vaccine to the US populations, as the efficacy of preventing severe and critical disease in all populations studied provides optimism for the overarching goal of emerging from the COVID-19 pandemic to a more normal lifestyle.

Additionally, the Johnson & Johnson vaccine was 77% effective in preventing severe or critical COVID-19 infections that occurred at least 14 days after vaccination with a total of 14 severe or critical cases in the vaccinated group versus 60 in the placebo group.⁸ At least 28 days after vaccination, the vaccine was 85% effective in preventing severe or critical infection with 5 severe or critical cases in the vaccine group versus 34 cases in the placebo group.⁸ Information about the severe or critical cases in the vaccination group were not provided in regards to health status prior to vaccination, and demographic factors.

Johnson and Johnson vaccine use of fetal tissue

The Johnson and Johnson vaccine used PER.C6, a fetal retinal cell originally isolated from fetal tissue from 1985, in various stages of vaccine development and manufacturing.⁹ The use of fetal cell lines is a very sensitive topic with religious individuals and faith-based communities, and also an ethical dilemma about how the fetal tissue is derived (eg, electively aborted fetal tissue from decades ago).

On March 11, 2021, Bishops in the Catholic Church, highly influential faith-based leaders, voiced moral concerns about taking the Johnson & Johnson vaccine.¹⁰ However, on March 24, 2021, the US conference of Catholic Bishops openly supported having the members of the Roman Catholic faith receive the Johnson & Johnson COVID-19 vaccine.¹¹

Comparison of Pfizer and Moderna vaccines to the Johnson & Johnson Vaccine

The Pfizer and Moderna vaccines are messenger ribonucleic acid (mRNA) vaccines with benefits of not generating infectious components or causing infection, and not affecting the genes or genome of the person or host cells.¹² The Pfizer BNT162b2 mRNA vaccine is a lipid nanoparticle-formulated vaccine that encodes a spike protein of the SARS-CoV-2 virus.⁴ The Moderna mRNA-1273 vaccine also encodes the spike protein and is similar to the Pfizer vaccine.¹ Once these vaccines are administered, the mRNA protein is processed by immune cells that produce the targeted protein and activate B cells and T cells to recognize the newly produced viral protein and make antibodies against SARS-CoV-2.¹³ These vaccines can be rapidly produced in a large-scale to treat mass populations, but do require freezer storage until shortly before administration.^12,13 A 2-dose regimen are recommended for both the Pfizer and Moderna vaccines.^1,4 Vaccine efficacy for the Pfizer and Moderna vaccines were both high with evidence of near complete protection in phase 3 clinical trials. The vaccine efficacy for Pfizer was 95% and the vaccine efficacy for Moderna was 94% and both vaccines were 100% effective in prevention of severe or critical COVID-19 cases.^1,4 No fetal tissue is used in development or production of vaccine.

In comparison to the Pfizer and Moderna vaccines, the Johnson and Johnson vaccine is a recombinant vector vaccine that uses a modified adenovirus vector that can no longer replicate and result in illness to express the SARS-CoV-2 spike protein.³ This vaccine is a single dose that can be stored in a refrigerator for months.³

COVID-19 vaccine clinical trials for children and adolescents

Pfizer: In July 2020, Pfizer began enrolling children aged 12 years and older in clinical trials with approximately 1000 between the ages of 12 to 15 years and 754 adolescents aged 16 to 17 years.¹⁴ In March 2021, Pfizer began enrolling children aged 6 months to 11 years in a Phase 1/2/3 clinical trial to determine if the vaccine can produce an immune response in young children and if it is safe.¹⁴ In addition, Pfizer is currently enrolling pregnant women in a RCT, as the EUA did not include pregnant women and left that decision to the women and their health care providers.14 In addition, Pfizer is studying phase 1 participants by administering a third dose 6 months after the completion of the original 2 doses were completed to understand the immunity against the variants that have emerged after the initial RCT.15

Pfizer BioNTech: On March 31, 2021, Pfizer provided a press release on the results of their clinical trial in adolescents aged 12 to 15-years. They enrolled 2260 adolescents in the United States in the clinical trial and plan to submit as an amendment the results to the FDA for EUA within the next few weeks. They reported on the phase 3 results of the clinical trial for the adolescent study participants who entered the study with or without previous exposure to COVID-19 disease. The press release reported 100% efficacy and a robust antibody response to the vaccine and exceeded the results of the clinical trials that enrolled 16- to 25-year-old adolescents and young adults.¹⁶

Moderna: The RCT for children aged 6 months to younger than 12 years has been registered on the National Institutes of Health US Library of Medicine Clinical Trials website for the Moderna mRNA-1273 COVID-19 vaccine.¹⁷ They are planning to enroll 6750 children. In Part 1 of the clinical trial, they will determine the dosage for the Moderna vaccine for the children. In Part 2, they will enroll participants into the RCT clinical trial with the treatment group to receive 2 doses of the dosage selected from the Part 1 dose investigation and dose 2, 29 days later. The control group will receive 2 doses of 0.9% sodium chloride injections, 29 days apart.¹⁷

Johnson & Johnson Vaccine: Janssen Biotech, the maker of Johnson & Johnson vaccine, announced shortly after receiving FDA EUA approval for its 1 dose COVID-19 vaccine for adults aged 18 years and older, that they plan to conduct clinical trials on children. The first trial will be for children aged 12 years and older, followed by trials for infants aged 6 months to 11 years. Details about the plans for the RCT for infants and children have not been published at this time.¹⁸

Vaccine talking points

Adolescents and young adults entering college are confronted, in some states, with mandates to return to school fully vaccinated in the Fall 2021 semester, and parents are contemplating whether their adolescents and young adults should be vaccinated and whether to vaccinate their younger children when the vaccines become available to them. Pediatricians and PNPs need to share 1 forward thinking message for adolescents and parents. Vaccines recommended by the FDA and the newly EUA COVID-19 vaccines are safe and effective and everyone who is eligible for the COVID-19 vaccine should take the vaccine without hesitation.

Conclusions

Safe and effective vaccines are available to prevent SARS-CoV-2 and fight the pandemic. However, vaccine hesitancy remains a barrier to effective vaccination of the community. Knowledgeable health care providers who provide clear messaging on the COVID-19 vaccine and the vaccines available, currently Johnson and Johnson, Pfizer, and Moderna and likely others in the future, should educate adolescents and their parents and encourage vaccine acceptance. In addition, all manufacturers are currently conducting RCTs for these vaccines in children.

References

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2. Sadoff, J. et al. Interim Results of a Phase 1–2a Trial of Ad26.COV2.S Covid-19 Vaccine. The New England Journal of Medicine, Accessed on March 29, 2021. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2034201DOI: 10.1056/NEJMoa2034201

3. National Institutes of Health (2021, January 29). Janssen Investigational COVID-19 Vaccine: Interim Analysis of Phase 3 Clinical Data Released. Accessed March 25, 2021. Retrieved from https://www.nih.gov/news-events/news-releases/janssen-investigational-covid-19-vaccine-interim-analysis-phase-3-clinical-data-released

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5. Pfizer-Biontech. Pfizer Biontech announces positive topline results of pivotal COVID-19 vaccine study in adolescents. Pfizer-Biontech Press Release. Accessed March 31, 2021. Retrieved April 1, 2021 from https://www.pfizer.com/news/press-release/press-release-detail/pfizer-biontech-announce-positive-topline-results-pivotal#:~:text=(NYSE%3A%20PFE)%20and%20BioNTech,exceeding%20those%20recorded%20earlier%20in

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8.U.S. Food and Drug Administration. FDA Issues Emergency Use Authorization for Third COVID-19 Vaccine. Accessed April 1, 2021. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-issues-emergency-use-authorization-third-covid-19-vaccine

9.Wadman, M. Vaccines that use human fetal cells draw fire. Science. 2021; 368(6946):1170-1171. doi: 10.1126/science.368.6496.1170

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14.Pfizer Biontech development program. Accessed March 29, 2021. Retrieved March 30, 2021 from https://www.pfizer.com/science/coronavirus/vaccine/rapid-progress

15.Studies to address emerging variants Accessed March 30, 3021. Retrieved March 30, 2021 from https://www.pfizer.com/science/coronavirus/vaccine/emerging-variants

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17.NH U.S. National Library of Medicine Clinical trials. A Study to Evaluate Safety and Effectiveness of mRNA-1273 Vaccine in Healthy Children Between 6 Months of Age and Less Than 12 Years of Age. Accessed March 30, 2021. Retrieved from https://clinicaltrials.gov/ct2/show/NCT04796896

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19. Centers for Disease Control and Prevention [CDC]. (2011). Ten great public health achievements United States 2001-2010. Morbidity and mortality weekly report, [MMWR], 60, 619-623. Accessed April 5, 2021. Retrieved April 5, 2021 form https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6019a5.htm