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Vaccines FAQ

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Last reviewed: September 20, 2022

Developed by the COVID-19 Real Time Learning Network Editorial Staff with input from Drs. Robin Avery, Michael Boeckh, Andrea Cox, Anna Durbin, Kathy Edwards, Hana El Sahly, Josh Hill, Mike Ison, Catherine Liu, Kathy Neuzil, Paul Offit, Tom Shimabukuro and Keipp Talbot.

Featured FAQs

Q: What is known about the Omicron variant of SARS-CoV-2?

A: The Omicron variant (B.1.1.529) was identified as a “variant of concern” by the World Health Organization in November 2021. The earliest sample known to contain this variant was collected in South Africa on Nov. 9, 2021.

The Omicron variant differs from previous variants of SARS-CoV-2 in the increased number of mutations present in the spike protein (37), relative to previous variants such as Beta (10) and Delta (9). These mutations may have implications for diagnostic testing, transmissibility and neutralization by vaccine-induced antibodies.

For more details and literature about Omicron, please visit our SARS-CoV-2 variants page

Q: Who should get a COVID-19 vaccine booster and when?

A: In the U.S., CDC recommends everyone ages 5 years and older receive a COVID-19 vaccine booster after completing their primary COVID-19 vaccination series. For up-to-date guidance and evidence synthesis, refer to our Vaccine Dosing & Schedule page. 

Q: What is waning immunity and how do we know if it is occurring?

A: Waning immunity refers to a phenomenon where an individual’s initial immune response to a vaccine diminishes over time and thus makes them vulnerable to natural infection (despite vaccination), often referred to as “breakthrough infection.” There is now extensive evidence that COVID-19 vaccine-induced antibodies decrease over time (Bánki, July 2022), and these reductions in antibodies may be related to gradual waning of immunity against SARS-CoV-2 (Vokó, July 2022), especially in the additional context of emerging SARS-CoV-2 variants. However, reductions in antibodies may have varying implications for clinical protection against severe COVID-19, and antibodies are boosted immediately following booster vaccination (Ng, August 2022).

Evidence for whether waning immunity is leading to “waning protection” is almost always indirect because there are many factors that can influence vaccine effectiveness over time that are independent of waning immune responses. In fact, observations of waning protection, which may be suggested by lower population-level vaccine effectiveness estimates over time or rates of breakthrough infection out of proportion to what is expected, need not be attributable to waning immune responses.

Q: What is known about “mixing and matching” vaccine doses of different types?

A: 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. Existing evidence from the U.K., the U.S. and Brazil suggests that heterologous dosing does not pose additional safety concerns and is effective (Munro, December 2021; Atmar, March 2022; Costa Clemens, February 2022), including during the Omicron phase (Seidel, July 2022).

For up-to-date guidance and evidence synthesis, refer to our Vaccine Dosing & Schedule page. 


Efficacy of COVID-19 Vaccines 

Q: How effective are current COVID-19 vaccines against emerging SARS-CoV-2 variants of concern? 

A: The Phase 3 trials of most currently available COVID-19 vaccines began prior to the emergence of most SARS-CoV-2 variants of concern; therefore, their efficacy against these variants can only be extrapolated from post-authorization observational studies conducted in countries where these vaccines are in use and where variants are highly prevalent. Data from ongoing clinical trials of mRNA COVID-19 vaccines in pediatric populations recently submitted to FDA (Pfizer-BioNTech: children 6 months–4 years; Moderna: individuals 6 months–17 years) suggest that while these vaccines have robust immunogenicity in pediatric populations, functional vaccine efficacy may still be low against the Omicron variant. These findings mirror observational studies of vaccine effectiveness against the Omicron variant in non-pediatric populations (for more information, see the Real-Time Learning Network’s summary section about vaccine effectiveness against SARS-CoV-2 variants of concern). Although the Phase 3 trials of the Novavax recombinant subunit vaccine began later than the initial Phase 3 trials of mRNA vaccines, most individuals included in study data presented to FDA were enrolled before Delta became a dominant circulating strain in the U.S (Novavax FDA Briefing Document, June 2022 [PDF]).

Of note, vaccine effectiveness can be measured using a variety of different outcomes, including prevention of transmission (which would encompass reduction in asymptomatic and symptomatic infections), reduction in symptomatic illness and reduction in severe disease, hospitalization or death due to COVID-19. Although all these outcomes may be relevant from a public health perspective, prevention of severe disease, hospitalization and death are most relevant to the individual vaccine recipient.  

The Real-Time Learning Network has assembled a summary of available data about vaccine and monoclonal antibody effectiveness against SARS-CoV-2 variants of concern, focusing on two outcomes: symptomatic infection and severe disease. Most of the available vaccine effectiveness data pertain to mRNA COVID-19 vaccines (largely Pfizer-BioNTech) or the Oxford-AstraZeneca COVID-19 vaccine. Finally, comparative vaccine effectiveness data depend on which variants were co-circulating at the time the analysis was done, thus estimates of vaccine effectiveness against Alpha were compared with ancestral strains (e.g., D614G), whereas estimates of vaccine effectiveness against Delta are compared with Alpha.

Q: Are the mRNA vaccines more efficacious than the viral vector vaccines? 

A: None of the COVID-19 vaccines have been directly compared head-to-head in the same population, and so the point estimates of vaccine efficacy for the mRNA vaccines (Moderna and Pfizer-BioNTech) and viral vector vaccines (Johnson & Johnson/Janssen and Oxford-AstraZeneca) cannot be directly compared with each other. The clinical trials for these vaccines were conducted at different times in different populations. Furthermore, the outcomes used to calculate the efficacy estimates differed between the studies (see previous question). The Pfizer-BioNTech, Moderna and Johnson & Johnson/Janssen vaccines have all been evaluated for emergency use authorization and met the efficacy criteria pre-specified by the FDA. They all have high efficacy, especially against severe COVID-19. 

Q: What do we know about breakthrough SARS-CoV-2 infections in vaccinated individuals? 

A: Our knowledge of SARS-CoV-2 breakthrough infections after vaccination is still evolving. Importantly, breakthrough infections occur at a lower incidence compared with infections in unvaccinated individuals, therefore the occurrence of breakthrough infections does not diminish the critical importance of vaccination against COVID-19. However, the risk of breakthrough infections appears to be higher for circulating variants of concern, compared to the ancestral SARS-CoV-2 strain.

To date, data suggest that many breakthrough infections are associated with mild illness or are asymptomatic. There are insufficient published data on the virologic and immunologic aspects of breakthrough infections to be able to draw definitive conclusions regarding risk assessment (for breakthrough infection) after vaccination, transmissibility of breakthrough infection (symptomatic or asymptomatic) or appropriate management. Below are critical summaries of selected reports of breakthrough SARS-CoV-2 infections in the published literature:

  • In an analysis of breakthrough SARS-CoV-2 infections reported to CDC between January 1, 2021, and April 30, 2021, investigators described 10,262 cases, of which 27% (N=2,725) were asymptomatic, 10% (N=995) were hospitalized at the time of their infection, and 2% (N=160) died. Notably, 29% of hospitalized patients with a reported breakthrough infection were asymptomatic or hospitalized for another reason, and 18% of the deaths were asymptomatic at the time their breakthrough infection was identified or died from another cause. Only 5% (N=555) of the breakthrough infections had sequencing data available, and nearly two-thirds (64%, N=356) were identified as variants of concern.  
  • In one of the largest case series of breakthrough infections reported to date, CDC investigators described a cluster of SARS-CoV-2 infections associated with large public gatherings in Barnstable County, Massachusetts. This investigation described 469 COVID-19 cases, of which 346 (74%) occurred in fully vaccinated individuals. Notably, of the 133 infections for which genome sequencing data were available, 119 (89%) were due to the Delta variant. Of the 346 breakthrough cases, 274 (79%) reported symptoms, four (1.2%) were hospitalized, and none died. In this study, the investigators reported cycle threshold values as a surrogate for viral load and noted that the median Ct values in vaccinated individuals were similar to those who were unvaccinated, partially vaccinated or with unknown vaccination status. 
    • Key limitations of this report include: incomplete data on the exposed population (which limits our ability to assess the relative incidence of infection in vaccinated and unvaccinated individuals); use of a surrogate measure of viral load (that does not distinguish between culturable virus, total RNA or subgenomic RNA); and no description of the approach to viral detection (specimen type, timing of specimen in course of illness, etc.). 
  • In a study of breakthrough infections captured in the Danish National Microbiology database, among 6076 participants, 127 and 364 breakthrough infections occurred due to Delta and Omicron variants, respectively (Staerke, August 2022). This study also identified that increasing age was associated with a reduced risk of breakthrough infections, and increasing community-level transmission of SARS-CoV-2 was associated with increased risk of breakthrough infections. Of 504 breakthrough infections, only one was identified as a case of severe COVID-19 disease requiring hospital admission; nine additional patients required outpatient treatment including monoclonal antibodies and/or remdesivir. 

Q: What is known about the impact of COVID-19 vaccination on SARS-CoV-2 transmission? 

A: There are limited data about the transmissibility of SARS-CoV-2 breakthrough infections, and apart from isolated case reports (Kernéis, August 2021), most of what is known is based on indirect evidence. Transmissibility depends on a variety of factors, including (but not limited to) the magnitude and duration of viral shedding. Prior to the emergence of the Delta variant, there was some evidence that COVID-19 vaccination may be associated with lower peak viral loads (Levine-Tiefenbrun, March 2021). Others have found lower Ct values (associated with higher peak viral loads) in breakthrough infections during periods of Delta circulation (Abu-Raddad, January 2022; Luo, August 2022), or little change in Ct value according to Delta versus Omicron infection, and according to vaccinated versus unvaccinated status (Fall, May 2022). Importantly, the increased transmissibility of the Delta variant has been attributed to higher viral loads and earlier viral shedding compared with ancestral strains of SARS-CoV-2 (Li, January 2022), which may have implications for the effect of COVID-19 vaccines on transmission of Delta. In a study of Delta infections in Singapore, the investigators evaluated viral and serologic kinetics of infection in vaccinated and unvaccinated individuals. They found that although both vaccinated and unvaccinated individuals had similar initial cycle threshold values, Ct values increased much faster (e.g., viral loads decreased much faster) in vaccinated individuals compared with unvaccinated individuals (Chia, November 2021). Prior to the emergence of Delta, in two large studies of household contacts of vaccinated and unvaccinated individuals with SARS-CoV-2 infection in the U.K. (Shah, October 2021) and the Netherlands (de Gier, August 2021), the risk of secondary infection was lower in contacts of vaccinated individuals compared with unvaccinated individuals.

Existing evidence from observational studies in Ontario, Canada (published by Public Health Ontario) suggests that Ct values for Omicron cases change slightly by vaccination status, but all Omicron cases had a median Ct value <25. Preliminary evidence from a large observational study in Israel suggests that while recent vaccination may reduce viral load (measured using Ct value as a proxy) for Omicron cases, this effect wanes quickly after vaccination (Woodbridge, March 2022 – preprint, not peer-reviewed).

Safety of COVID-19 Vaccines

Q: What is the association between COVID-19 vaccines and myocarditis/pericarditis?  

A: For up-to-date information, refer to the myocarditis section of our Vaccine Safety page.  

Q: In comparing the different types of COVID-19 vaccines available in the U.S., which is the safest and will have fewest side effects for people? 

A: Although the benefits of vaccination with any COVID-19 vaccine still outweigh the risks posed either by vaccination or by COVID-19 infection, CDC has expressed a clinical preference for eligible individuals to receive Pfizer-BioNTech or Moderna mRNA vaccine or Novavax recombinant subunit vaccine over Johnson & Johnson/Janssen vaccine, given abundant supply of these types of vaccines and their rare risk of adverse events. In May 2022, FDA restricted authorization of Johnson & Johnson/Janssen vaccine to adults 18 years and older who were medically ineligible to receive another COVID-19 vaccine, or who otherwise would not receive another COVID-19 vaccine.

A final Phase 3 analysis of the Johnson & Johnson/Janssen vaccine followed 39,185 participants (8,940 participants with at least 6 months of follow-up) and included 6,736 participants in a safety sub-analysis (Sadoff, March 2022). In this sub-analysis, participants were asked to record solicited local and systemic adverse events for 7 days after vaccine administration and unsolicited adverse events for 28 days after vaccine administration. Grade 3 local and systemic solicited adverse events were similar in vaccinated versus unvaccinated individuals, with symptoms of injection site pain, fatigue, headache, myalgia, nausea and fever slightly more common in vaccinated individuals. Statistical imbalances were seen for tinnitus (15 cases in vaccine vs. four in placebo group), urticaria (13 in vaccine vs. six in placebo group), convulsion (nine vs. four), pulmonary embolism (10 vs. five), and deep-vein thrombosis (11 vs. three); overall, adverse events were rare in both groups. Reports from VAERS (the Vaccine Adverse Event Reporting System), an early-warning system set up to monitor potential vaccine safety concerns, suggest that Johnson & Johnson/Janssen vaccine may be associated with a higher risk of thrombosis with thrombocytopenia syndrome (Shimabukuro, May 2021). In a large-scale study conducted in the U.S. Vaccine Safety Datalink (VSD), Johnson & Johnson/Janssen vaccine was associated with a moderately higher risk of Guillain-Barré syndrome after vaccination, compared to baseline rates of Guillain-Barré syndrome (Hanson, April 2022).

Phase 3 analyses of Novavax vaccine are still ongoing. Additionally, observational studies that make head-to-head safety comparisons of different COVID-19 vaccine modalities for rare conditions are still ongoing.

COVID-19 Vaccination by Patient Population

Q: What is the benefit of vaccinating individuals who have had COVID-19? 

A: Multiple studies have shown that previously infected individuals mount a robust immune response following receipt of COVID-19 vaccines, even after just a single dose. Furthermore, there are accumulating data that vaccination after prior infection can boost immune responses against SARS-CoV-2 variants of concern — in fact, the vaccine response in previously infected individuals may be superior to that in individuals without prior infection (Wang, June 2021Stamatatos, June 2021Reynolds, June 2021Lyski, December 2021Bates, January 2022; Urbanowicz, August 2021). 

Although the clinical trials of COVID-19 vaccines excluded seropositive individuals from their efficacy calculations, there are emerging data that vaccination can also confer protection against reinfection. In a case-control study of SARS-CoV-2 reinfections in Kentucky, investigators found that individuals who had had natural infection in 2020 and who did not receive a vaccine had 2.34 times the odds of reinfection compared with individuals who had natural infection and then subsequently received a COVID-19 vaccine (Cavanaugh, August 2021). 



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