Last Reviewed: February 22, 2022
- 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 5-15 using the same schedule. The vaccine dose is 30 mcg for ages 12 and up, but is 10 mcg for children 5-11 years old.
- The Moderna COVID-19 vaccine is FDA-approved for 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.
FDA has authorized and CDC recommends 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 percentage virus neutralization was 71% in the vaccine group compared with only 13% in the placebo group (Hall, August 2021). In a secondary analysis of this trial, the authors also found that a third dose of vaccine augmented neutralizing antibody responses against the Alpha, Beta and Delta variants (Kumar, November 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 one and 40% after dose two — this increased to 68% after dose three. Among the individuals who were seropositive after dose two, antibody titers also increased after dose three (from 36±12 to 2676±350). Finally, of the 59 individuals who were seronegative after dose two, 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's 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).
In the U.S., all adults aged 18 and older should receive a single booster dose of any COVID-19 vaccine under a revised eligibility policy that was FDA-authorized and CDC-recommended in November 2021. Single booster doses of any product approved or authorized in the U.S. may be administered at least five months after completion of a primary mRNA vaccination series or at least two months after primary vaccination with the single-dose J&J/Janssen COVID-19 vaccine.
FDA has also authorized the use of booster doses for individuals aged 12-17 who received the Pfizer-BioNTech vaccine.
In an analysis of safety data gathered through the v-safe surveillance system, booster doses were overall safe and were associated with fewer reactogenicity events than second doses of mRNA vaccine (Hause, February 2022).
Booster doses augment immune responses (quantitatively or qualitatively) against SARS-CoV-2 (and relevant variants).
Data for augmented immune responses following booster doses come from several studies. In a substudy of the Phase I clinical trial of the Pfizer-BioNTech COVID-19 vaccine, 23 participants received a booster dose of the vaccine at approximately 8 months after completion of the primary series. One month after the booster dose, neutralizing antibody titers against both wildtype virus and the Beta (B.1.351) and Delta (B.1.617.2) variants had increased to levels higher than at one month after the primary series (Falsey, September 2021). In another study of 97 Israeli healthcare workers aged 60 years and up who received a third dose of the Pfizer-BioNTech COVID-19 vaccine approximately 6-7 months after their primary series, the additional vaccine dose significantly increased anti-spike IgG antibody titers measured 10-19 days after vaccination (Eliakim-Raz, November 2021).
The two largest studies were multicenter studies that compared the safety and immunogenicity of a variety of different booster vaccines, including heterologous doses. In an interim analysis of a multicenter trial conducted at 10 sites in the U.S., the investigators reported immune responses following heterologous and homologous booster doses among >400 participants who had previously been vaccinated with either two doses of an mRNA COVID-19 vaccine or one dose of the Johnson & Johnson/Janssen COVID-19 vaccine (at least 12 weeks earlier). In this study, a booster dose with any product augmented antibody concentrations, but heterologous boosts (“mixed” regimens) elicited a more robust response than homologous boosts (“matched” regimens) (Atmar, January 2022).
In another large study conducted in the UK, the investigators reported immune responses following heterologous and homologous boosters among >2800 participants who had previously received either two doses of the Oxford-AstraZeneca or Pfizer-BioNTech COVID-19 vaccine (at least 10-12 weeks earlier). Participants were randomized to receive boosts with the Oxford-AstraZeneca, Pfizer-BioNTech, Moderna, or Johnson & Johnson/Janssen COVID-19 vaccines, as well as the Novavax COVID-19 vaccine, the CureVac mRNA COVID-19 vaccine, and an inactivated vaccine. All the booster vaccines augmented immune responses following a Pfizer-BioNTech COVID-19 vaccine series, with the two currently authorized mRNA COVID-19 vaccines demonstrating the greatest effect (Munro, December 2021).
The durability of these augmented immune responses is unknown. In a longitudinal study of immune responses to SARS-CoV-2 following mRNA COVID-19 vaccination (mostly the Pfizer-BioNTech COVID-19 vaccine), the investigators separately analyzed the kinetics of the immune response in individuals with and without prior SARS-CoV-2 infection. For those with prior infection, the primary vaccine series may be considered a “booster.” In this group, antibody, memory B-cell and T-cell responses were augmented by vaccination but had declined nearly back to baseline by 6 months (Goel, October 2021).
Booster doses lead to increased vaccine effectiveness against COVID-19.
Multiple studies have evaluated the clinical effectiveness of a COVID-19 vaccine booster dose. These are mostly observational cohort studies during time periods when either Delta or Omicron were the predominant circulating variants. Together, the data indicate that a booster dose of an mRNA COVID-19 vaccine (i.e., a third dose given several months after a two-dose primary series) provides a significant protective effect against symptomatic COVID-19 (Bar-On, September 2021; Saciuk, November 2021; Patalon, November 2021; Bar-On, December 2021), COVID-19 hospitalization and death compared with two doses of vaccine (Barda, October 2021; Arbel, December 2021; Andrews, January 2022).
The emergence of the Omicron variant and its capacity for immune escape also motivated a number of studies to evaluate the benefits of booster doses. Booster doses of mRNA COVID-19 and the Johnson & Johnson/Janssen COVID-19 vaccines appear to restore in vitro neutralization titers (Nemet, December 2021; Garcia-Beltran, December 2021; Pajon, January 2022; Lyke, January 2022 – pre-print, not peer reviewed) as well as clinical effectiveness (Andrews, December 2021 – preprint, not peer-reviewed; Thompson, January 2022; Johnson, January 2022; Accorsi, January 2022; Gray, December 2021 – pre-print, not peer-reviewed; Hui Xuan Tan, February 2022; Ferdinands, February 2022). As an example, in a non-peer-reviewed analysis of SARS-CoV-2 infections in the U.K. following the emergence of the Omicron variant, the authors found that two doses of the Pfizer-BioNTech COVID-19 vaccine demonstrated a vaccine effectiveness against symptomatic COVID-19 (presumed due to Omicron) of 88.0% (95% CI, 65.9-95.8%) 2-9 weeks after dose 2, 48.5% (95% CI, 24.3-65.0%) at 10-14 weeks post dose 2, and 34-37% from 15 weeks post dose 2 – two weeks after a booster dose with the Pfizer COVID-19 vaccine, vaccine effectiveness had increased to 75.5% (95% CI, 56.1-86.3%) (Andrews, December 2021 – pre-print, not peer-reviewed).
The durability of this improvement in vaccine effectiveness is poorly characterized. In an analysis of urgent care encounters, emergent department visits, and hospitalizations due to COVID-19 in the VISION Network in the US, investigators found waning effectiveness of a third (booster) dose of mRNA COVID-19 vaccines against all three outcomes after 2 months, during both the Delta and Omicron waves. Notably, booster dose effectiveness waned more significantly against urgent care and emergency department encounters, but was more durable against hospitalization, remaining greater than 75% for up to 4 months after vaccination during both time periods (Ferdinands, February 2022).
In the U.S., CDC currently recommends completing a primary series of a two-dose vaccine (or three doses for certain immunocompromised patients) with the same product, whenever possible. For booster vaccination, FDA has authorized the use of heterologous (or “mix and match”) booster doses for currently available COVID-19 vaccines (i.e., FDA-authorized or approved). Interim CDC guidance addresses clinical considerations related to heterologous booster doses, including patient benefit-risk considerations when selecting which booster dose to receive.
There have been few studies evaluating a mixed product primary series with the vaccines currently available in the U.S. The largest such study, the Com-COV2 trial, was conducted in the U.K. and compared the safety and immunogenicity of two doses of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines with heterologous schedules containing one dose of either followed by one dose of either the Moderna or Novavax COVID-19 vaccine (Stuart, December 2021). The safety and immunogenicity of a vaccine series containing two doses of the Pfizer-BioNTech vaccinewere similar to a vaccine series containing one dose of Pfizer-BioNTech followed by one dose of Moderna. Antibody and cellular response were slightly higher in the mixed schedule group, which may be attributable to the higher antigen content in the Moderna vaccine rather than any benefit of a mixed schedule per se.
The Com-COV2 trial and other studies outside the U.S. have also evaluated mixed schedules containing one dose of an mRNA vaccine and one dose of the Oxford-AstraZeneca vaccine (which is based on a similar technology to the Johnson & Johnson/Janssen COVID-19 vaccine), though the time between the first and second dose of vaccine in these studies has been variable. 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) 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, November 2021; Schmidt, September 2021; Tenbusch, July 2021; Dimeglio, August 2021). In some studies, a heterologous schedule containing one Oxford-AstraZeneca and one mRNA COVID-19 vaccine dose 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; Kaku, February 2022).
Some studies suggest that heterologous boosters may be superior to homologous boosters. Per CDC guidance, mRNA COVID-19 boosters are preferred over the Johnson & Johnson/Janssen COVID-19 vaccine. Data to support this recommendation come from studies on immunogenicity (Atmar, January 2022; Munro, December 2021; Sablerolles, January 2022) and clinical effectiveness (Mayr, February 2022; Hui Xuan Tan, February 2022).
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 below.
mRNA vaccine interval
There is accumulating evidence that a longer interval between the two doses of mRNA COVID-19 vaccines may confer improved immunogenicity and potentially even clinical effectiveness. Studies in the U.K. and Canada have demonstrated that a longer time period (ranging from 6-16 weeks depending on the study) between the two doses of both the Pfizer-BioNTech and Moderna COVID-19 vaccines is associated with increased antibody and cellular responses (Parry, August 2021; Grunau, November 2021; Grunau, December 2021; Payne, November 2021). A separate analysis in the U.K. of 750 adults aged 50-79 years confirmed these findings, and further demonstrated that an interval of >45 days between dose one and two of the Pfizer-BioNTech COVID-19 vaccine was associated with improved vaccine effectiveness (over a follow-up period that preceded emergence of the Delta variant) against SARS-CoV-2 infection (Amirthalingam, December 2021).
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).
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.