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Commentary: Additional COVID-19 Vaccine Doses

01/12/2021 Matthew E. Levison, MD, Drexel University College of Medicine|Drexel University;

Confusion is widespread in the wake of multiple, at times conflicting, often ambiguous announcements regarding additional doses of the COVID-19 vaccines. Starting on August 1, 2021, Israel, the first country to do so, deployed a third mRNA vaccine dose. Initially, this third dose was given to people over the age of 60 years, but eventually, everyone aged 12 years and up who received the second mRNA COVID-19 vaccine dose at least five months previously was eligible for a third dose (1). Other countries, including the UK, Germany, France, Hungary, and Russia were already planning to administer an additional COVID-19 vaccine dose to selected portions of their populations.


At the same time, the World Health Organization (WHO), raising ethical issues, was recommending against additional COVID-19 vaccine doses for anyone. The WHO noted that there was no strong evidence for providing an additional dose to fully vaccinated people in medically well-served nations while people in medically underserved nations are still unvaccinated, particularly because COVID-19 vaccines are holding up extremely well at protecting against severe disease, hospitalization, and death, even against variants of SARS-CoV-2 (the virus that causes COVID-19) currently in circulation. If people in medically underserved countries remain unvaccinated, rampant viral transmission will continue as new viral variants that resist immune control evolve, eventually finding their way around the world. In other words, nobody is safe until everyone worldwide has had the opportunity to be vaccinated (2). The US countered that “boosting” in the US is aimed at addressing perceived domestic needs, while the US is donating additional vaccine doses to other countries in need of COVID-19 vaccines (3).


More recently (10/11/2021), however, the WHO’s Strategic Advisory Group of Experts (SAGE) recommended “immunocompromised people be given an additional dose of COVID-19 vaccine, due to their higher risk of breakthrough infections after standard immunization,” consistent in part with the US CDC’s current policy (4).


Multiple doses of a vaccine are commonly required to assure an adequate immune response. A primary series, usually consisting of 2 or more vaccine doses, is necessary to achieve the highest possible levels of immunity. In addition to the primary series, a booster dose is often necessary to restore an effective immune response that has faded over time. For example, the primary series for the diphtheria, pertussis, and tetanus vaccine is 3 doses that are given to children at ages 2, 4, and 6 months. In the US, a booster dose to restore a waning immune response is given at age 12 to15 months and a second booster dose is given at age 4 to 6 years (5). Additional booster doses of a tetanus vaccine are then given to adults every 10 years to maintain an effective immune response.


Influenza vaccinations are repeated annually for a different reason. Because influenza viruses frequently change genetically, influenza vaccines are updated each year to maintain an effective immune response against the influenza virus currently circulating in the population. So far, SARS-CoV-2 virus variants in circulation have responded well to immune control induced by the current COVID-19 vaccines. But some future variants may emerge that will escape the immune response induced by currently used COVID-19 vaccines, and vaccine developers anticipate that updated vaccines that better target these emerging variants will be needed.


SARS-CoV-2’s spike protein is a structure projecting from the viral surface that serves as a key that binds the virus to the host cell-surface receptors, initiating viral entry into the host cell. All current COVID-19 vaccines stimulate the immune system to make antibody to the spike protein, blocking viral entry. Currently, 3 COVID-19 vaccines are authorized for use in the US: Two are messenger RNA (mRNA) vaccines, one manufactured by Pfizer-BioNTech (Pfizer) and the other manufactured by Moderna, and an adenovirus-vectored vaccine manufactured by Johnson and Johnson/Jansen (J&J). The Pfizer and Moderna vaccines are currently given in a 2-dose regimen, with 3 weeks between the first and second dose for the Pfizer vaccine and 4 weeks for the Moderna vaccine. The Johnson and Johnson vaccine is currently given as a single dose.


Should an additional vaccine dose be considered just one of the doses in a primary series or a booster dose? Certainly, for people who were not fully vaccinated by the initial vaccine dose(s), for example, in those whose immune system is weakened, the additional dose is being given in an attempt to fully vaccinate and is considered part of a primary series. For those who were fully vaccinated by the primary vaccine dose(s) but whose immune response has begun to fade over time, an additional dose is given to boost the immune response.


Testing to assess the adequacy of the immune response following COVID-19 vaccination is not currently recommended because the minimum level of antibody that affords protection is not yet known. To evaluate for evidence of prior COVID-19 infection in vaccinated people, a different blood test is used that specifically evaluates for the presence of antibody to the SARS-CoV-2.


Additional COVID-19 vaccine doses for PEOPLE WITH A WEAKENED IMMUNE SYSTEM


On August 12, 2021, after evaluating studies in organ transplant patients with weakened immune systems that showed COVID-19 vaccine effectiveness was low and that an additional dose of the vaccines increased production of antibodies against the SARS-CoV-2 virus, the FDA amended the emergency use authorizations (EUAs) so that people with this level of immunocompromise could receive a third dose of either the Pfizer or Moderna COVID-19 vaccine (6). The CDC recommended that people who are moderately to severely immunocompromised (aged 12 years and older for Pfizer or aged 18 years and older for Moderna) receive an additional dose of the same COVID-19 vaccine they originally received at least 28 days after the completion of the initial COVID-19 vaccine series (7, 8).


People eligible for a third dose include:

Solid organ transplant recipients who are taking medicine to suppress the immune system

Those who received a stem cell transplant within the last 2 years or are taking medicine to suppress the immune system

Those undergoing cancer treatment

Those with advanced or untreated HIV infection

Those with autoimmune diseases who are receiving drugs that suppress their immune systems, such as high doses of corticosteroids or other drugs that may suppress the immune system

Those with moderate or severe primary immunodeficiency disorders (such as DiGeorge syndrome or Wiskott-Aldrich syndrome)


CDC recommendations for an additional vaccine dose in people who are moderately to severely immunocompromised only apply to people who had previously received the Pfizer or Moderna vaccines (9), because there is not enough data at this time to say whether immunocompromised people who received Johnson & Johnson COVID-19 vaccine will have an improved antibody response following an additional dose of the same vaccine.


Immunocompromised people should maintain non-pharmaceutical precautions (for example, masking, physical distancing, etc) to help prevent COVID-19. In addition, close contacts of immunocompromised people should be vaccinated to provide additional protection.


Additional COVID-19 vaccine doses for PEOPLE WHO ARE NOT immunocompromised


A recently published study (10) confirmed that the effectiveness of the Pfizer vaccine against SARS-CoV-2 infections had declined over the study period from 88% within 1 month after receiving 2 vaccine doses to 47% after 6 months. During the study period, the percent of cases attributed to the delta variant had risen from 0.6% in April 2021 to nearly 87% in July 2021, and vaccine effectiveness against delta variant infections, which was 93% at 1 month after 2 doses, fell to 53% after 4 months; however, effectiveness against delta-related hospitalizations remained high (93%) for the duration of the study period for all ages. Reductions in the vaccine’s effectiveness against infections over time was thought likely to be due to waning immunity, rather than the delta variant escaping vaccine protection.


In contrast to the declining effectiveness of the Pfizer vaccine, the effectiveness of the Moderna vaccine against COVID-19 hospitalization has been reported to be stable (93% at 14–120 days after the 2nd vaccine dose and 92% at > 120 days). Moderna submitted data to the FDA on September 1, 2021, supporting its proposed booster dose containing half the amount of mRNA than is in the original formulation (11). It's not clear whether the lower dose would result in fewer side effects.


The FDA and CDC have approved Pfizer and Moderna booster doses for all adults 18 years and older to be given 6 months after completing the 2-dose series with any of the COVID-19 vaccines authorized in the United States, even with a vaccine different from the one used in the primary series (12, 13).


Booster dosing is especially important in older people (those 50 years of age or older), because they are at much greater risk of severe illness from COVID-19 (14). Booster dosing is also especially important in those individuals 18 years of age or older living in long-term care settings, because of the communal nature of living in long-term care facilities and the populations served (adults often with advanced age or underlying medical conditions that put these individuals at increased risk of infection and severe illness from COVID-19---15).


The CDC has recommended that people should be offered vaccination regardless of their history of symptomatic or asymptomatic SARS-CoV-2 infection, including those with prolonged post-COVID-19 symptoms. However, vaccinations should be deferred until recovery from acute illness, and criteria have been met to discontinue isolation (16).


People who previously received antibody therapy as part of COVID-19 treatment should defer vaccination for at least 90 days after receipt of passive antibody therapy (monoclonal antibodies or convalescent plasma) because evidence suggests that reinfection is uncommon within the 90 days after initial infection.


The story on the Johnson & Johnson vaccine is different. A single dose of the Johnson & Johnson vaccine has lower vaccine effectiveness than the 2-dose mRNA primary series. The CDC recommends that all people 18 years and older who received the Johnson & Johnson vaccine should get a second (booster) dose 2 months after receiving the initial dose with any of the COVID-19 vaccines authorized in the United States. (13).




1 TOI Staff: Over 1 million Israelis who haven’t had 3rd dose to lose Green Pass on Sunday. Times of Israel September 21, 2021.


2. Cramer M, Gross J: Some are chasing vaccine shots while scientists debate. New York Times July 29, 2021, updated October 11, 2021.


3. Keith T: The U. S. is donating more COVID vaccines and wants other rich nations to pitch in. NPR September 22, 2021.


4. Nebehay S, Farge E: WHO advises additional COVID shot for immunocompromised people. Reuters October 11, 2021.


5. U. S. Centers for Disease Control and Prevention: Vaccines for Your Children. Atlanta, CDC. Updated November 23, 2021.


6. US Food and Drug Administration: Coronavirus 19 (COVID-19) update. FDA authorizes additional vaccine dose for certain immunocompromised individuals [News release]. August 12, 2021.


7. US Centers for Disease Control and Prevention: COVID-19 vaccines for moderately to severely immunocompromised people. Atlanta, CDC, October 18, 2021.


8. US Centers for Disease Control and Prevention. COVID-19 Vaccines for moderately to severely immunocompromised people. Atlanta, CDC Updated November 23, 2021.


9. Hause AM, Baggs J, Gee J, et al: Safety monitoring of an additional dose of COVID-19 vaccine---August 12-September 19, 2021. MMWR 70(39):1379-1384, 2021.


10. Tartof SY, Slezak JM, Fischer H, et al: Effectiveness on mRNA BNT162b2 COVID-19 vaccine up to six months in a large integrated health system in the USA: a retrospective cohort study. Lancet 398(10309): P1407-1416, 2021.


11. Moderna announces submission of initial data to U. S. FDA for its COVID-19 vaccine booster. September 1, 2021.


12. US Centers for Disease Control and Prevention: Some COVID-19 vaccine recipients can get booster shots. October 27, 2021.


13. US Centers for Disease Control and Prevention: COVID-19 vaccine booster shots. Atlanta, CDC. Updated November 29, 2021.


14. Morris J: Israeli data: how can efficacy vs. severe disease be strong when 60% of hospitalized are vaccinated? COVID-19 Data Science August 17, 2021.


15. Chidambaram P, Garfield R: Patterns in Covid-19 cases and deaths in long-term care facilities in 2020. KFF [Henry J. Kaiser Family Foundation]. January 14, 2021.


16. US Centers for Disease Control and Prevention: Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Atlanta, CDC. November 5, 2021.
Matthew Levison, MD

Test your knowledge
Lymphocytopenia is an abnormally low number of white blood cells in the blood. Lymphocytopenia can be acute, occurring briefly during certain conditions, or it can be chronic, occurring for a longer period of time. In addition to viral infections, which of the following is the most common cause of chronic lymphocytopenia?