Last Reviewed: October 15, 2021
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- Additional Doses
- Mixed Products
The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.
The three COVID-19 vaccines available for use in the U.S. follow various dosing schedules:
- The Pfizer-BioNTech COVID-19 vaccine is FDA-approved for use as a two-dose series administered 21 days apart to adolescents and adults 16 years and older and is authorized for emergency use in children ages 12-15 using the same schedule.
- The Moderna COVID-19 vaccine is FDA-authorized for emergency use as a two-dose series administered 28 days apart to adults 18 years and older.
- The Johnson & Johnson/Janssen COVID-19 vaccine is FDA-authorized for emergency use as a one-dose series for adults 18 years and older.
All three vaccines have been demonstrated to be highly effective against severe outcomes related to COVID-19 in clinical trials and post-authorization observational studies. However, given concerns about waning immunity and the emergence of novel variants, there is interest in understanding the potential role of alternative dosing strategies for these vaccines to augment or prolong their protective effect, including (but not limited to): administration of additional doses of each vaccine, schedules containing different products (“mix and match”) and modified dosing intervals.
Additional doses of COVID-19 vaccines can serve two purposes:
- As part of the primary vaccine series, to augment the initial immune response (for example, the U.S. now recommends a routine third dose of mRNA vaccines for certain immunocompromised groups); or
- As a booster dose after the primary series is complete, to reinforce the immune response (for example, an additional dose months or years after completion of the primary series).
This use of an additional vaccine dose is to augment the initial immune response to COVID-19 vaccination. This strategy has primarily been studied in individuals who are likely to have a suboptimal response following two doses of an mRNA COVID-19 vaccine. Multiple small studies (see below) of individuals with comorbidities associated with a weakened response to vaccination (e.g., solid organ transplantation, hematologic malignancy, or end-stage renal disease) suggest that additional doses of mRNA COVID-19 vaccines can increase antibody concentrations in these individuals. In short-term follow-up, these additional doses appear to be safe.
Notably, because there is no immunologic correlate of protection against SARS-CoV-2 infection (i.e., immunity cannot be inferred from the results of current available antibody tests), how these findings translate into vaccine effectiveness remains unknown. In addition, the relevance of these findings to the general (non-immunocompromised) population is not clear.
In August 2021, FDA authorized and CDC recommended a third dose of COVID-19 mRNA vaccine as part of the primary series for certain immunocompromised populations.
Key primary studies that have evaluated the effect of additional doses of COVID-19 vaccines as part of a primary series in immunocompromised populations include:
- In a randomized controlled trial of 120 solid organ transplant recipients, subjects who had previously completed a two-dose series of the Moderna COVID-19 vaccine were randomized 1:1 to receive a third dose of vaccine or saline placebo 2 months after the second dose of the primary vaccine series. Immunogenicity data were available from 117 subjects; prior to the study intervention, only 11.7% and 8.8% of the treatment and placebo groups respectively had an anti-receptor binding domain antibody concentration above a pre-specified threshold of 100 U/mL. At 1 month after the study intervention, 55% (33 of 60) recipients of a third dose of Moderna COVID-19 vaccine achieved that concentration, compared with only 18% (10 of 57) in the placebo group. Additionally, after the study intervention the median percent virus neutralization was 71% in the vaccine group compared with only 13% in the placebo group (Hall, August 2021).
- In a prospective study of 101 solid organ transplant recipients (78 kidney, 12 liver, eight lung or heart and three pancreas) in France, the investigators evaluated immune responses to a third dose of the Pfizer-BioNTech COVID-19 vaccine administered approximately two months (61±1 day) after the second dose. The proportion of individuals with detectable anti-SARS-CoV-2 antibodies was 0% at baseline, 4% after dose 1 and 40% after dose 2 — this increased to 68% after dose 3. Among the individuals who were seropositive after dose 2, antibody titers also increased after dose 3 (from 36±12 to 2676±350). Finally, of the 59 individuals who were seronegative after dose 2, 44% (n=26) became seropositive after the third dose (Kamar, June 2021). The same group of investigators reported similar findings in an expanded cohort of 396 solid organ transplant recipients, which included data from the 101 described previously (Del Bello, July 2021).
- In a prospective study of 159 kidney transplant recipients in France, the investigators evaluated immune responses to a third dose of the Moderna COVID-19 vaccine administered approximately 2 months (median 51 days) after the second dose. The patients selected for this study had to have an antibody response below the cutoff for positivity at baseline (i.e., after two prior doses of Moderna vaccine). Nearly half (n=78, or 49%) of patients developed an antibody response above the cutoff for positivity after a third dose of vaccine. Compared with patients who had had no response to prior doses of vaccine, those with a weak response demonstrated a more robust response to a third dose (27.4% vs. 81.3%) (Benotmane, July 2021).
- In a non-peer-reviewed observational study of 43 patients with lymphoid malignancies (13 with chronic lymphocytic leukemia, 14 with non-Hodgkin lymphoma and 16 with multiple myeloma) who had received a third dose of Pfizer-BioNTech COVID-19 vaccine in France, the investigators noted that 18 (41.8%) had no baseline antibody response to prior doses of vaccine. None of these patients developed an antibody response after a third dose. Of note, 14 (77.8%) of these individuals had previously received B cell depleting therapy. The third dose of vaccine did elicit higher antibody titers in the majority (23 of 25) of individuals who had at least some baseline antibody response after two doses of vaccine (Re, July 2021 - preprint, not peer-reviewed).
- In an observational study of 30 solid organ transplant recipients who received a third dose of a COVID-19 vaccine in the United States, 15 individuals (10 kidney, three liver, one heart, one pancreas) who had previously completed a two-dose series of an mRNA vaccine received a third dose of an mRNA vaccine (six received the same mRNA vaccine product, nine received the other mRNA vaccine product). Four of these individuals had a positive anti-SARS-CoV-2 antibody concentration at baseline, and nine individuals (60%) had a positive result after a third dose (including the four who were seropositive at baseline) (Werbel, June 2021). A follow-up study using the same cohort found that sera from some solid organ transplant recipients who received a third dose of an mRNA COVID-19 vaccine demonstrated greater pseudoneutralization against SARS-CoV-2 variants of concern, though this activity was still lower than of sera from healthy control individuals that had received only two doses of vaccine (Karaba, August 2021 – preprint, not peer-reviewed).
Viral vector vaccines
- In an observational study of 30 solid organ transplant recipients who received a third dose of a COVID-19 vaccine in the United States, 15 individuals (12 kidney, one kidney-pancreas, one heart, one lung) who had previously completed a two-dose series of an mRNA vaccine received an additional dose of the Johnson & Johnson/Janssen COVID-19 vaccine. Only one of these individuals had a positive antibody response at baseline, and five (33%) had a positive antibody response after the third dose, including the one who was positive at baseline (Werbel, June 2021).
There is no current recommendation to offer a third dose of COVID-19 vaccine as part of the primary series to immunocompetent individuals. There are limited data on the effect of a third dose used in this context.
- No data in immunocompetent individuals.
Viral vector vaccines
- In a longitudinal immunogenicity study of the Johnson & Johnson/Janssen COVID-19 vaccine, investigators evaluated antibody and cellular responses 8 months after a first dose of that vaccine, including in 10 healthy individuals who had received a second dose of the vaccine 2 months after the first dose. Neutralizing antibody titers at the 8-month time point were not significantly different between individuals who had received one or two doses as part of their primary series (Barouch, July 2021).
This use of an additional COVID-19 vaccine dose after the primary series is complete is intended to re-restimulate (i.e., prolong) immunity in individuals whose initial immune response may have waned over time. This may have the added effect of enhancing (i.e., broadening) protection against emerging variants of concern. The formulation of these booster doses may be identical to the vaccines administered as part of the primary series, or they may be reformulations designed to generate an immune response against specific variants; both are under investigation.
In the U.S., Pfizer, Moderna and Johnson & Johnson/Janssen have each submitted applications seeking FDA approval for administration of a booster dose after the primary series. In September 2021, FDA amended the Pfizer-BioNTech COVID-19 vaccine's emergency use authorization to permit administration of one booster dose at least six months after completion of the primary series.
According to subsequent CDC recommendations, eligible populations include:
- Adults 65 years of age and older;
- Adults age 50–64 with underlying medical conditions;
- Residents of long-term care settings aged 18 years and older;
- Adults age 18-49 with underlying medical conditions at high risk of severe COVID-19; and
- Adults age 18-64 who live or work in high-risk occupational or institutional settings.
For now, booster doses are only available to members of these populations who initially received the Pfizer-BioNTech COVID-19 vaccine.
In October 2021, FDA’s Vaccines and Related Biological Products Advisory Committee voted unanimously (19-0) to approve both the Moderna and Johnson & Johnson/Janssen booster shot proposals. CDC’s Advisory Committee on Immunization Practices will meet on October 20, 2021 to finalize subsequent clinical recommendations.
To date, there are still limited published data on the immunogenicity and clinical effectiveness of booster doses of COVID-19 vaccines, and this strategy has only been adopted by some countries.
Key primary studies that have evaluated the effect of booster doses of COVID-19 vaccines are summarized here:
mRNA vaccine boosters
- In a retrospective cohort study of vaccinated individuals in Israel (which approved booster doses of the Pfizer-BioNTech COVID-19 vaccine for individuals aged 60 years and older who had completed their primary vaccine series at least 5 months earlier), investigators analyzed the rates of COVID-19 among those who had and those who had not received a booster dose. Israel began administering booster doses on July 30, 2021, and the follow-up period of this study ended on Aug. 30, 2021. (For severe COVID-19 the end date was Aug. 26, 2021.) The investigators limited the primary analysis of COVID-19 illnesses to those that occurred at least 12 days after the booster dose; thus, the maximum possible follow-up period for any given individual was 20 days. Overall, the investigators found a lower rate of confirmed infection in the booster group (by a factor of 11.3; 95% CI, 10.4 to 12.3), as well as a lower rate of severe illness in the booster group (by a factor of 19.5; 95% CI, 12.9 to 29.5) (Bar-On, September 2021).
- In a longitudinal immunogenicity substudy of the Phase 1 clinical trial of the Pfizer-BioNTech COVID-19 vaccine, 23 participants received a 30 μg booster dose at approximately 8 months after completion of the primary series. In these individuals, neutralizing antibody titers against wildtype SARS-CoV-2 had decreased six- to 13-fold over the 8 months after the second dose of vaccine. One month after the booster dose, neutralizing antibody titers against both wildtype virus and the beta and delta variants had increased. Notably, the post-booster antibody titers were higher than the levels achieved at 1 month after the primary series and actually increased from day 7 to 1 month after the booster, in contrast to the waning that was observed from day 7 to 1 month after the second dose (Falsey, September 2021).
- Data from a longitudinal immunogenicity study of participants in the Phase 1 and Phase 2/3 clinical trials of the Pfizer-BioNTech COVID-19 vaccine were reviewed by VRBPAC in response to Pfizer’s BLA supplement seeking approval for a booster dose of its COVID-19 vaccine. This analysis included immunogenicity data from 329 participants (n=23 participants from the Phase 1 study, n=306 participants from the Phase 2/3 study) who had received a booster dose of the Pfizer-BioNTech COVID-19 vaccine. The median interval between completion of the primary series and the booster dose was 8.3 months (range, 7.9-8.5) for Phase 1 participants, and 6.8 months (range, 4.8-8.0) for Phase 2/3 participants. Following the booster dose, the median follow-up time was 2.6 months (range, 2.1-2.9) for Phase 1 participants and 2.6 months (range, 1.1-2.8) for Phase 2/3 participants.
In this analysis, neutralizing antibody concentrations (50% neutralizing geometric mean titers) at 1 month after the booster dose were approximately threefold higher than those observed at 1 month after the primary series. There was also an exploratory analysis to evaluate the impact of the booster dose on immune responses against the delta variant, which was limited to 23 participants whose sera were tested using a nonvalidated SARS-CoV-2 plaque reduction neutralization assay. In this exploratory analysis, neutralizing antibody titers against the delta variant were more than five-fold higher at 1 month after the booster dose compared with 1 month after the primary series.
- A press release from Moderna described results of a study of 344 participants enrolled in a Phase 2 study of the Moderna COVID-19 vaccine, including immunogenicity data following a 50 µg booster dose given 6 months following completion of the primary series. In this press release, neutralizing antibody titers following the booster dose exceeded those described in the Phase 3 trial. Additionally, the booster dose elicited robust antibody responses against SARS-CoV-2 variants of concern, including beta (B.1.351), gamma (P.1) and delta (B.1.617.2).
Viral vector vaccine boosters
- In a longitudinal immunogenicity study of participants in the Phase 1 and Phase 2 studies of the Johnson & Johnson/Janssen COVID-19 vaccine, investigators evaluated antibody and cellular responses 6 months after a first dose of that vaccine, as well as immune responses after a homologous booster dose given to 90 individuals (17 received a high-dose booster of 5 x 1010 viral particles, and 73 received a low-dose booster of 1.25 x 1010 viral particles) at 6 months after the first dose. At 4 weeks after the booster dose, antibody titers were higher than those measured at day 29 after the initial dose (nine-fold higher among recipients of the high-dose booster, and 6.4-fold higher among recipients of the low-dose booster) (Sadoff, August 2021 – preprint, not peer-reviewed).
- In a sub-study of the COV001 and COV002 clinical trials of the Oxford-AstraZeneca COVID-19 vaccine in the U.K., investigators described the immunogenicity of a third dose of that vaccine given 28-38 weeks after the first two doses in 75 healthy subjects. The third dose of vaccine generated significantly higher antibody responses at 28 days after the third dose, as well as higher neutralizing antibody titers against three variants of concern (alpha, beta and delta) (Flaxman, September 2021).
“Mixed-product” vaccine schedules — using more than one vaccine type to complete a series — are not currently recommended in the U.S., with exceptions permissible if the product needed to complete a two-dose vaccine series is not available at the time of the second dose, or the individual experienced a severe adverse event related to the first dose (making the second dose contraindicated).
However, given the availability of multiple vaccine formulations and ongoing development of additional vaccine products (e.g., nanoparticle and subunit vaccines), there is considerable interest in understanding the safety and efficacy of a “mixed” or heterologous vaccine schedule.
To date, there are no published data about the immunogenicity or efficacy of a mixed schedule that includes currently authorized mRNA vaccines (Pfizer-BioNTech or Moderna) combined with the Johnson & Johnson/Janssen COVID-19 vaccine. Several studies outside the U.S. have evaluated heterologous schedules containing mRNA vaccines and the Oxford-AstraZeneca COVID-19 vaccine, though the time between the first and second dose of vaccine in these studies has varied.
Most of these studies have concluded that a two-dose schedule that includes both vaccines, in either order, generates a robust antibody and cellular response compared with a single dose of either vaccine. Furthermore, in the studies where a heterologous and homologous (i.e., containing two doses of the same vaccine product) schedule were directly compared, the safety profile and immune responses with both schedules appeared to be similar (Borobia, June 2021; Shaw, May 2021; Liu, August 2021; Ostadgavahi, May 2021; Hillus, August 2021; Schmidt, June 2021- preprint, not peer-reviewed; Tenbusch, July 2021; Dimeglio, August 2021).
In one study, a heterologous schedule containing the Oxford-AstraZeneca and Pfizer-BioNTech COVID-19 vaccines elicited a more robust cellular response and higher neutralizing antibody titers against SARS-CoV-2 variants than a homologous schedule containing two doses of the Oxford-AstraZeneca vaccine (Barros-Martins, July 2021).
The interval between doses of two-dose COVID-19 vaccines may impact their immunogenicity and clinical effectiveness. However, to date there are limited data for this strategy; therefore, alternative schedules are not currently recommended.
Key primary studies that have evaluated the effect of alternate COVID-19 vaccine schedules are summarized here:
mRNA vaccine interval
- In a prospective cohort study of 172 individuals aged 80 years or older in the U.K., investigators compared peak antibody and cellular responses against SARS-CoV-2 spike protein among those who received their second dose of vaccine 3 weeks after the first dose (standard interval) or 11-12 weeks after the first dose (extended interval). Immune response was measured at 5-6 weeks and 13-14 weeks after dose 1 in both groups; thus, the “peak” response in the standard interval cohort was assessed at the first time point, whereas the “peak’ response in the extended interval cohort was assessed at the second time point. In this study, the peak antibody response was 3.5-fold higher in the extended interval group (Parry, May 2021 – preprint, not peer reviewed).
Viral vector vaccine interval
- In an exploratory analysis of a Phase 3 randomized controlled trial of the Oxford-AstraZeneca COVID-19 vaccine, investigators evaluated the impact of variable timing of the second dose of vaccine. In this analysis, vaccine efficacy against primary symptomatic COVID-19 (starting 14 days after the second dose) was higher with longer dose intervals. Vaccine efficacy was 55.1% (95% CI, 33.0–69.9) when the interval between the two doses was less than 6 weeks, and 81.3% (60.3–91.2) when the interval was more than 12 weeks (Voysey, February 2021).
Coadministration (with non-COVID-19 vaccines)
Per CDC recommendations, COVID-19 vaccines can be administered without regard to timing of other vaccines. Of note, the effect of coadministration or closely spaced administration of COVID-19 and non-COVID-19 vaccines on immunogenicity and reactogenicity has not yet been well characterized.