Data on 600 subjects tested blind in the P201 study with two half doses, 50 micrograms of Moderna vaccine, showed production of an equal amount of antibody to the 100-microgram chosen dose, but no clinical studies were done to show relative clinical efficacy. Notably, in the over 55-year-old group, there was a slight decrease in the bAB response in those given a higher 100 microgram vaccine dose.10
There is also a need to look for specific T-reg lymphocytes that suppress Covid-19 immunity in those administered the full initial dose of the Astra Zeneca and Moderna vaccines, and possibly with the other vaccines as well.
Berzofsky’s group summarizes T-cell subset and antibody responses to antigen dose in vaccine and shows that lower antigen dose can yield more sensitive T-cell response, higher quality T-cell receptors, and higher quality and affinity antibodies. Antibody production requires T-cell help. High avidity T-cells came from stimulation with low primary antigen concentrations. Low-dose antigen stimulates enhanced protection. T-reg cell, follicular T-helper cells, and subset ratios are all dependent on priming antigen dose. Age, infectious agent involved, timing,11 and adjuvant also affect response, and sufficiently lowering the dose can increase viral sensitivity and effectiveness of the vaccine, or even lower it, depending on interaction on a variety of other factors. The complexity of these later observations supports lowering the antigen dose, but the myriad of specific interactive factors, including higher antigen dose favors antibody production but not memory B-cell production, might explain why a fifty-percent reduction is more optimal clinically than a still greater dose reduction.
The initial priming vaccine dose followed by a repeat dose of vaccine 28 days later has a distinct resemblance to those priming and re-stimulation studies. The observation we made offers a possible scientific explanation of the reportedly puzzling finding and could account for the greater protection with a smaller dose of antigen and should stimulate further studies on the underlying immunologic mechanism of the phenomenon we observed. Lower dose clinical and in vitro studies are needed for the various vaccines, to see if lower initial and secondary Covid-19 vaccine doses give better immunity after the secondary vaccine priming as in our study.
This data does not prove the need for lower dose vaccine administration. It supports the need for further investigation, including a properly monitored volunteer subgroup given half the vaccine dose, in the current experimental vaccine rollout, while following clinical results in all, as well as laboratorytested immune parameters on a sample of that group, all compared with clinical results and immune parameters in a sample of those receiving full-dose immunization. This dose reduction could improve vaccine protection, enable more people to be vaccinated with the current output, and reduce second vaccine side effects, as seen with the Oxford half initial dose administration.12 Since the vaccine rollout is still on an experimental basis, there is no reason to hesitate with a trial of a reduced dose already found to give a higher percentage of protection.
There is also a need to look for specific T-reg lymphocytes that suppress Covid-19 immunity in those administered the full initial dose of the Astra Zeneca and Moderna vaccines, and possibly with the other vaccines as well.
Berzofsky’s group summarizes T-cell subset and antibody responses to antigen dose in vaccine and shows that lower antigen dose can yield more sensitive T-cell response, higher quality T-cell receptors, and higher quality and affinity antibodies. Antibody production requires T-cell help. High avidity T-cells came from stimulation with low primary antigen concentrations. Low-dose antigen stimulates enhanced protection. T-reg cell, follicular T-helper cells, and subset ratios are all dependent on priming antigen dose. Age, infectious agent involved, timing,11 and adjuvant also affect response, and sufficiently lowering the dose can increase viral sensitivity and effectiveness of the vaccine, or even lower it, depending on interaction on a variety of other factors. The complexity of these later observations supports lowering the antigen dose, but the myriad of specific interactive factors, including higher antigen dose favors antibody production but not memory B-cell production, might explain why a fifty-percent reduction is more optimal clinically than a still greater dose reduction.
The initial priming vaccine dose followed by a repeat dose of vaccine 28 days later has a distinct resemblance to those priming and re-stimulation studies. The observation we made offers a possible scientific explanation of the reportedly puzzling finding and could account for the greater protection with a smaller dose of antigen and should stimulate further studies on the underlying immunologic mechanism of the phenomenon we observed. Lower dose clinical and in vitro studies are needed for the various vaccines, to see if lower initial and secondary Covid-19 vaccine doses give better immunity after the secondary vaccine priming as in our study.
This data does not prove the need for lower dose vaccine administration. It supports the need for further investigation, including a properly monitored volunteer subgroup given half the vaccine dose, in the current experimental vaccine rollout, while following clinical results in all, as well as laboratorytested immune parameters on a sample of that group, all compared with clinical results and immune parameters in a sample of those receiving full-dose immunization. This dose reduction could improve vaccine protection, enable more people to be vaccinated with the current output, and reduce second vaccine side effects, as seen with the Oxford half initial dose administration.12 Since the vaccine rollout is still on an experimental basis, there is no reason to hesitate with a trial of a reduced dose already found to give a higher percentage of protection.
CONCLUSION
In conclusion, this study offers not only a mechanism to
explore this apparent low-dose paradox, but also the important
possibility that a much smaller dose of vaccine could be
effective, extending or even doubling the number of people
who could now be immunized by the currently available
vaccine. That could greatly speed the ending of this Covid-19
pandemic on a world-wide basis, especially during a race for
control against appearance of new, more aggressive genetic
variants of SARS-Cov-2.
DISCLOSURES
The authors have no declaration of interests and have no
relevant interests to declare.
REFERENCES
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2. AstraZeneca press statement. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19. (23 November 2020). Available at: https:// www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html.
3. Lawton G. Do Oxford/AstraZeneca covid-19 vaccine results stand up to scrutiny? New Scientist. 2020;27 November.
4. Dattner AM, Levis WR. Unresponsiveness induced by priming human leukocyte cultures with optimal stimulating concentrations of a soluble protein antigen. IRCS J Med Sci. GB; DA. 1977;5:411-412.
5. Dattner AM, Levis WR. Restoration of accelerated blastogenesis to previously unresponsive high-dose-PPD unresponsive paralyzed clonally primed lymphocytes. IRCS J Med Sci. GB; DA. 1977;5:526.
6. Dattner AM, Levis WR. Clonal priming of human lymphocytes with soluble microbial antigens: high-dose paralysis, restoration, and autologous leukocyte preference. Scand J Immunol. 1978;8:403-12. doi: 10.1111/j.1365- 3083.1978.tb00535.
7. Dattner AM, Levis WR. Specific and nonspecific immunoregulatory events in the clonal response of human lymphocytes in vitro. Scand J Immunol. 1980;11:169-74. doi: 10.1111/j.1365-3083.1980.tb00223.
8. Kurnick JT, Hayward AR, Altevogt P. Helper and suppressor-inducer activity of human T cells and their cloned progeny maintained in long-term culture. J Immunol. 1981;126:1307-11.
9. Kurnick JT, Grönvik KO, Kimura AK, Lindblom JB, Skoog VT, Sjöberg O, Wigzell H. Long term growth in vitro of human T cell blasts with maintenance of specificity and function. J Immunol. 1979;122:1255-60.
10. Vaccines and Related Biological Products Advisory Committee Meeting December 17, 2020. FDA Briefing Document Moderna COVID-19 Vaccine. Available at: https://www.fda.gov/media/144434/download p11, 53, 54
11. Billeskov R, Beikzadeh B, Berzofsky JA. The effect of antigen dose on T cell-targeting vaccine outcome. Human Vaccines and Immunotherapeutics. 2019;15:2:407-411, DOI: 10.1080/21645515.2018.1527496.
12. Stecklow S, MacAskill A. Exclusive: Oxford kept COVID-19 vaccine trial volunteers in dark about dosing error, letter shows. February 1, 2021. Available at:https://www.reuters.com/article/us-health-coronavirus-vaccine-oxfordexc/ exclusive-oxford-kept-covid-19-vaccine-trial-volunteers-in-dark-aboutdosing- error-letter-shows-idUSKBN2A1263
2. AstraZeneca press statement. AZD1222 vaccine met primary efficacy endpoint in preventing COVID-19. (23 November 2020). Available at: https:// www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html.
3. Lawton G. Do Oxford/AstraZeneca covid-19 vaccine results stand up to scrutiny? New Scientist. 2020;27 November.
4. Dattner AM, Levis WR. Unresponsiveness induced by priming human leukocyte cultures with optimal stimulating concentrations of a soluble protein antigen. IRCS J Med Sci. GB; DA. 1977;5:411-412.
5. Dattner AM, Levis WR. Restoration of accelerated blastogenesis to previously unresponsive high-dose-PPD unresponsive paralyzed clonally primed lymphocytes. IRCS J Med Sci. GB; DA. 1977;5:526.
6. Dattner AM, Levis WR. Clonal priming of human lymphocytes with soluble microbial antigens: high-dose paralysis, restoration, and autologous leukocyte preference. Scand J Immunol. 1978;8:403-12. doi: 10.1111/j.1365- 3083.1978.tb00535.
7. Dattner AM, Levis WR. Specific and nonspecific immunoregulatory events in the clonal response of human lymphocytes in vitro. Scand J Immunol. 1980;11:169-74. doi: 10.1111/j.1365-3083.1980.tb00223.
8. Kurnick JT, Hayward AR, Altevogt P. Helper and suppressor-inducer activity of human T cells and their cloned progeny maintained in long-term culture. J Immunol. 1981;126:1307-11.
9. Kurnick JT, Grönvik KO, Kimura AK, Lindblom JB, Skoog VT, Sjöberg O, Wigzell H. Long term growth in vitro of human T cell blasts with maintenance of specificity and function. J Immunol. 1979;122:1255-60.
10. Vaccines and Related Biological Products Advisory Committee Meeting December 17, 2020. FDA Briefing Document Moderna COVID-19 Vaccine. Available at: https://www.fda.gov/media/144434/download p11, 53, 54
11. Billeskov R, Beikzadeh B, Berzofsky JA. The effect of antigen dose on T cell-targeting vaccine outcome. Human Vaccines and Immunotherapeutics. 2019;15:2:407-411, DOI: 10.1080/21645515.2018.1527496.
12. Stecklow S, MacAskill A. Exclusive: Oxford kept COVID-19 vaccine trial volunteers in dark about dosing error, letter shows. February 1, 2021. Available at:https://www.reuters.com/article/us-health-coronavirus-vaccine-oxfordexc/ exclusive-oxford-kept-covid-19-vaccine-trial-volunteers-in-dark-aboutdosing- error-letter-shows-idUSKBN2A1263
AUTHOR CORRESPONDENCE
Alan M. Dattner DoctorDattner@gmail.com
