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Vaccines FAQ

Last Reviewed: June 11, 2021

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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.

Mechanisms of COVID-19 Vaccines

Q: What are mRNA vaccines and how do they work?

A: mRNA vaccines contain messenger RNA, a single-stranded RNA molecule that encodes the vaccine antigen, or protein that elicits a protective immune response. Messenger RNA is normally created in the nucleus when DNA is transcribed by RNA polymerase to create pre-mRNA (Zipursky, 2000). Pre-mRNA is then spliced (segments are removed/rearranged) into mRNA, which is exported from the nucleus to the cytoplasm and “read” by ribosomes (the translation machinery of cells). Ribosomes then make proteins.

mRNA vaccines use lipid nanoparticles to deliver lab-created mRNA directly to the cytoplasm. Once the vaccine mRNA is in the cytoplasm, ribosomes can translate it, which results in the creation of a protein antigen that triggers an immune response (Schlake, November 2020). The vaccine mRNA does not enter the nucleus, and therefore cannot be incorporated into the genome. Its presence in the cell is transient, and it is quickly metabolized and eliminated via cellular processing mechanisms (Pardi, November 2015). Unlike conventional vaccines, which can take months to produce, mRNA vaccines can be created quickly and are more easily scaled because they use an organism’s genetic code.  

 

Q: Which COVID-19 vaccines are based on mRNA technology?

A: Two mRNA vaccines are available under emergency use authorization by FDA: the Pfizer-BioNTech COVID-19 vaccine and the Moderna COVID-19 vaccine, the latter of which was developed in partnership with the National Institute of Allergy and Infectious Diseases. Both vaccines are lipid nanoparticle-formulated, nucleoside-modified mRNA vaccines encoding the prefusion spike glycoprotein of SARS-CoV-2, the virus that causes COVID-19. A third mRNA vaccine, CVnCoV, has been developed by CureVac and is currently being evaluated in a Phase 3 clinical trial.

 

Q: What happens to the vaccine mRNA once it is in the cytoplasm?

A: The mRNA is degraded quickly by normal intracellular processes. The cell breaks down and gets rid of the mRNA soon after it has been translated by the ribosome. The mRNA does not enter the nucleus and is not extruded from the cell.

 

Q: Can the vaccine mRNA alter cellular DNA or RNA?

A: No. For the vaccine mRNA to alter someone’s DNA, several events would need to occur. First, the vaccine mRNA would need to enter the cell nucleus, where DNA resides. However, vaccine mRNA does not have the nuclear access signals that would allow it to enter the nucleus — it can’t get in. Second, even if it made it into the nucleus, the mRNA would have to be converted to DNA. This would require an enzyme called reverse transcriptase, which the mRNA vaccines (and human cells) don’t contain. Third, an enzyme (such as integrase) would be needed for DNA derived from the vaccine mRNA to insert itself into cellular DNA; the mRNA vaccines don’t contain such an enzyme.

The vaccine mRNA also cannot alter cellular RNA. The vaccine mRNA is delivered to the cytoplasm, where it is translated by ribosomes, resulting in the creation of the SARS-CoV-2 spike protein. The vaccine does not contain any splicing enzymes and the mRNA does not encode any proteins that would allow for RNA modification. Furthermore, the vaccine mRNA is not self-amplifying and cannot be transferred from cell to cell. Following translation, it is rapidly degraded. The vaccine mRNA remains in the cell cytoplasm for just a few days before it is destroyed (Pardi, November 2015). Of note, there are more than 200,000 cellular mRNAs per cell, each making a host of proteins and enzymes. The mRNA vaccines introduce only a few copies of mRNA into cells.  

In short, the mRNA vaccines lack all of the basic requirements necessary to alter DNA or RNA.

 

Q: What are viral vector vaccines and how do they work?

A: Viral vector vaccines utilize viruses to deliver genes that encode vaccine antigens into host cells (Vrba, November 2020). Genes of a pathogen — typically those that code for specific antigens that elicit a protective immune response — are first inserted into the genome of a viral vector. The vector is a virus different from the one the vaccine is targeting (for example, an adenovirus). The vaccine delivers the vector, which infects host cells; DNA virus vectors (like adenoviruses) then travel to the nucleus. In the nucleus, the genes of the pathogen are expressed, resulting in the creation of the antigen. The antigen is then expressed on the host cell surface, resulting in the induction of an immune response.

Viral vector vaccines can be replicating or nonreplicating:

  • Replicating viral vector vaccines infect cells, resulting in the production of the vaccine antigen. The viral vector is also produced and is then able to infect new cells, which then create more viral antigen. The only currently licensed replication-competent vaccines are the recombinant vesicular stomatitis virus (rVSV)-Zaire Ebola virus vaccine and the live attenuated tetravalent dengue vaccine.
  • Nonreplicating viral vector vaccines infect cells, resulting in the production of the vaccine antigen, but the viral vector cannot be reproduced (van Riel, July 2020). Several COVID-19 vaccines are based on this technology, including the Johnson & Johnson/Janssen, Oxford-AstraZeneca and Gam-COVID-Vac (Sputnik V) vaccines.

 

Q: Which COVID-19 vaccines are based on viral vector technology?

A: The Johnson & Johnson/Janssen COVID-19 is the only viral vector vaccine currently available in the U.S. under emergency use authorization by FDA. This vaccine uses a human adenovirus, Ad26, as the viral vector, and encodes for a stabilized variant of the SARS-CoV-2 spike protein.

The Oxford-AstraZeneca COVID-19 vaccine is another viral vector vaccine that has been authorized for use in many countries. This vaccine uses a chimpanzee adenovirus (ChAdOx1, which is based on ChAdY25) as the viral vector. It encodes for the spike protein of SARS-CoV-2. Finally, the Gam-COVID-Vac vaccine (Sputnik V), developed by the Gamaleya Research Institute of Epidemiology and Microbiology in Russia, is another viral vector vaccine that uses two human adenovirus vectors, (Ad26 and Ad5), both of which encode for the SARS-CoV-2 spike protein.

 

Q: What happens to the viral vector once it is in the cytoplasm?

A: The viral vectors enter the nucleus where the genome of the vector, including the gene encoding the vaccine antigen(s), are transcribed by host RNA polymerase into mRNA. The mRNA are exported to the nucleus, where they are transcribed into vaccine antigens. The viral vectors used in COVID-19 vaccines are non-replicating — this means they do not possess the machinery to generate more copies of themselves in vivo and they are degraded by the host cell once their genome has been transcribed.

 

Q: Can the viral vector alter cellular DNA?

A: No. The viral vectors used in COVID-19 vaccines do not integrate into the genome or contain the enzymes needed to insert vector DNA into cellular DNA. Once the viral vector DNA has been transcribed, the vector genome is degraded.

 

Q: Can the viral vector COVID-19 vaccines be transmitted in vivo?

A: No. The viral vector used in the Oxford-AstraZeneca and Johnson & Johnson/Janssen COVID-19 vaccines are replication incompetent (sometimes called replication deficient). This means they do not replicate within the human body, and there is no possibility for transmission of the viral vector to other individuals.

 

Q: What happens to the spike protein generated by the COVID-19 vaccines after it is produced by ribosomes?

A: The spike protein may exist in three different forms after translation within the cell. First, the protein can be presented on the cell surface in its native form. Second, the protein can also be processed within the cell into different peptides, which can be presented by major histocompatibility complex class I and MHC class II molecules. MHC proteins play a key role in the adaptive branch of the immune system, presenting peptides on the cell surface for recognition by T cells. Finally, the protein may also be secreted into the extracellular space, where it may be recognized by B cells (which make antibodies) or taken up by antigen presenting cells and re-processed. The protein may be found on the surface of the cell in either its peptide form or its native form, likely until the cell dies or interacts with other immune cells.

 

Q: How long does the spike protein made by the body (generated by the COVID-19 vaccines) last in the body?

A: The protein lasts the same amount of time as other proteins made by the body. The exact time is not known, but it is estimated to be a few weeks.

 

Efficacy of COVID-19 Vaccines

 

Q: What does “vaccine efficacy” mean, and how was efficacy measured in the Pfizer-BioNTech, Moderna, Johnson & Johnson/Janssen and Oxford-AstraZeneca COVID-19 vaccine trials?

A: Vaccine efficacy refers to the percent reduction in cases of a disease among individuals who receive a vaccine compared with those who are unvaccinated. The primary efficacy endpoint in all the trials was clinical disease, meaning symptomatic COVID-19; reduction in infection, which would include both symptomatic COVID-19 as well as any positive test for SARS-CoV-2 in the absence of symptoms, was not assessed as a primary endpoint, although additional data utilizing serologic endpoints are being collected in all the trials. When the term “vaccine efficacy” is discussed in relation to these vaccines, it generally refers to efficacy at preventing clinical disease unless otherwise specified.

The primary endpoints for the Phase 3 trials of these vaccines were as follows:

  • Pfizer-BioNTech: Efficacy against PCR-confirmed symptomatic COVID-19 with onset at least 7 days after the second dose of vaccine among participants without serologic or virologic evidence of prior SARS-CoV-2 infection at baseline.
  • Moderna: Efficacy against PCR-confirmed symptomatic COVID-19 with onset at least 14 days after the second dose of vaccine among participants without evidence of prior SARS-CoV-2 infection at baseline.
  • Johnson & Johnson/Janssen: Efficacy against PCR-confirmed moderate to severe/critical COVID-19 in the periods starting 14 days after vaccination and 28 days after vaccination among participants without evidence of prior SARS-CoV-2 infection at baseline.
  • Oxford-AstraZeneca: Efficacy against PCR-confirmed symptomatic COVID-19 starting 14 days after dose 2 of the vaccine.

 

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: When does immunity to symptomatic SARS-CoV-2 infection develop after completion of a COVID-19 vaccine series?

A: Our current knowledge regarding when vaccinated persons can expect to achieve a high level of protection from developing symptomatic COVID-19 is derived from the published clinical trial data. The Moderna COVID-19 vaccine demonstrated 95% efficacy for prevention of symptomatic COVID-19 starting 14 days after receiving the second dose; the Pfizer-BioNTech COVID-19 vaccine demonstrated 95% efficacy for prevention of symptomatic COVID-19 starting 7 days after receiving the second dose; the Johnson & Johnson/Janssen COVID-19 vaccine demonstrated 67% efficacy for prevention of moderate-severe/critical COVID-19 starting 14 days after vaccination; finally, the Oxford-AstraZeneca COVID-19 vaccine demonstrated 67% efficacy for prevention of symptomatic COVID-19 starting 14 days after receiving the second dose.

 

Q: What is the durability of immune response to COVID-19 vaccination? How long are people expected to be protected?

A: The durability of the immune response following COVID-19 vaccination has only been reported for the Moderna and Oxford-AstraZeneca COVID-19 vaccines. Follow-up immunogenicity data from a Phase 1 open-label dose escalation trial of the Moderna COVID-19 vaccine demonstrated antibody persistence through 209 days after the first vaccination with the 100-μg dose of mRNA-1273 (180 days after the second vaccination) that declined slightly over time (Doria-Rose, April 2021). Follow-up immunogenicity data from a Phase 3 trial of the Oxford-AstraZeneca COVID-19 vaccine demonstrated persistence of anti-SARS-CoV-2 spike IgG antibodies through 180 days after the first vaccination, though with a 64% decrease in geometric mean titers over that time period (Voysey, February 2021).

None of the ongoing clinical trials of currently authorized COVID-19 vaccines have published long-term follow-up efficacy data to draw firm conclusions on the durability of vaccine efficacy. However, all of the trials are continuing to collect data on durability of vaccine induced-immune responses.

 

Q: What is the efficacy of a single dose of the two-dose vaccines against symptomatic COVID-19, i.e., the Moderna, Pfizer-BioNTech and Oxford-AstraZeneca COVID-19 vaccines?

A: Single doses of the Pfizer-BioNTech, Moderna and Oxford-AstraZeneca COVID-19 vaccines have not been formally evaluated in clinical trials. Furthermore, the durability of protection after a single dose of any of the two-dose vaccines is unknown; therefore, it is still recommended that individuals complete the two-dose series of all the two-dose COVID-19 vaccines.

In a secondary analysis of data presented to FDA as part of the Moderna EUA application, the Moderna COVID-19 vaccine demonstrated 92% efficacy against symptomatic COVID-19 starting 14 days after the first dose of vaccine just through 28 days after the second dose (when participants received the second dose of the vaccine). Similarly, in a secondary analysis of the data that had been presented to FDA as part of the Pfizer-BioNTech EUA application, the Pfizer-BioNTech COVID-19 vaccine demonstrated 93% efficacy against symptomatic COVID-19 starting 14 days after the first dose of vaccine just through 21 days after the first dose (which is when participants received the second dose of the vaccine) (Skowronski, February 2021).

The efficacy of a single dose of the Oxford-AstraZeneca vaccine was evaluated in an exploratory analysis as part of a Phase 3 trial in which the timing of the second dose of vaccine was variable among study participants (Voysey, February 2021). In that analysis, a single dose of the vaccine was 76% effective against symptomatic COVID-19 starting 21 days after the first dose through 90 days.

 

Q: What do we know about the ability of the COVID-19 vaccines to prevent asymptomatic infection or viral transmission (i.e., spread)?

A: The primary efficacy endpoints of all the COVID-19 vaccine trials were clinical disease; however, all of the studies collected data that provide some insight on the ability of these vaccines to prevent asymptomatic infection, including surveillance nasopharyngeal swabs for SARS-CoV-2 viral testing and/or serologies. Since baseline serostatus was known in all these studies, if a subject converted from negative to positive serology during the trial in the absence of a COVID-19 illness, it would imply asymptomatic infection. Some of the vaccines have additionally been evaluated in post-authorization studies in various settings where they have been deployed. Here is a summary of what is known about the impact of each vaccine on asymptomatic infection:

  • Moderna: As part of the Phase 3 trial of mRNA-1273, investigators collected pre-dose 1 and pre-dose 2 nasopharyngeal swabs for SARS-CoV-2 viral testing and performed a descriptive study comparing the number of positive swabs at the pre-dose 2 time point in baseline seronegative participants. Amongst baseline negative participants, 15 participants in the vaccine group and 39 participants in the placebo group had evidence of SARS-CoV-2 infection at the second dose without evidence of COVID-19 symptoms. There were approximately two-thirds fewer swabs that were positive in the vaccine group as compared to the placebo group at the pre-dose 2 time point, suggesting that some asymptomatic infections start to be prevented after the first dose (Baden, February 2021).
  • Pfizer-BioNTech: Multiple post-authorization observational studies of BNT162b2 in diverse settings suggest that this vaccine is effective against asymptomatic infection.

Israel: In an observational study that used data from the largest of four integrated health services in Israel, vaccine effectiveness was 46% against SARS-CoV-2 infection (positive PCR, with or without symptoms) from 14-20 days after dose 1 and 92% against infection from 7 days after dose 2. In an exploratory analysis, vaccine effectiveness was 90% against asymptomatic infection based on a proxy measure of SARS-CoV-2 test positivity without documented symptoms (Dagan, February 2021). In a separate analysis of nationwide surveillance data, vaccine effectiveness was 91.5% against asymptomatic SARS-CoV-2 infection starting 7 days after dose 2 (Haas, May 2021).

United States: In an analysis of the incidence of new (asymptomatic) SARS-CoV-2 infections detected by weekly surveillance PCRs among health care workers at the University of California, San Diego and the University of California, Los Angeles health systems, there were only 7 new infections identified among those who had received their second dose of BNT162b2 15 or more days earlier, compared with 145 who had just received their first dose of vaccine in the preceding 7 days (and so would not be expected to be protected) (Keehner, March 2021). In another analysis of pre-procedural asymptomatic SARS-CoV-2 test positivity within the Mayo Clinic health system, investigators determined a 72% reduction in the risk of having a positive SARS-CoV-2 test among individuals who had received at least 1 dose of an mRNA vaccine (94% of subjects in the study had received BNT162b2) at least 10 days earlier (Tande, March 2021).

United Kingdom: An analysis of new SARS-CoV-2 infections among U.K. health care workers following a mass vaccination campaign with BNT162b2 identified 51 asymptomatic cases (no symptoms within 14 days before and after the date of a positive test) among unvaccinated individuals compared with only 10 in the vaccinated cohort (Hall, April 2021).

  • Johnson & Johnson/Janssen: As part of the Phase 3 trial of Ad26.COV2.S, investigators collected serology against SARS-CoV-2 N protein from study subjects at day 71 — since N protein is not contained in the vaccine, a conversion from negative to positive would imply natural SARS-CoV-2 infection. Of the 2,650 individuals who had an anti-N serology result at day 71, there were 18 asymptomatic infections in the vaccine group and 50 in the placebo group, for an estimated vaccine efficacy of 65.5% (Sadoff, April 2021).
  • Oxford-AstraZeneca: As part of the Phase 3 trial of ChAdOx1 conducted in the U.K. (COV002), study subjects submitted self-collected nose and throat swabs on a weekly basis for SARS-CoV-2 PCR testing. In a preliminary analysis of these data, the vaccine effectiveness against SARS-CoV-2 infection without symptoms (or where symptoms were unknown) was 47.2% if the interval between dose 1 and 2 of the vaccine was 12 weeks or greater (Voysey, February 2021). In a vaccine effectiveness analysis stratified by SARS-CoV-2 variant status, ChAdOx1 was 69.7% effective against asymptomatic infection due to non-B.1.1.7 variants, but demonstrated no protection against asymptomatic infection due to the SARS-CoV-2 B.1.1.7 variant (Emary, April 2021).

In summary, vaccinated individuals can develop asymptomatic infection, though at significantly lower rates than unvaccinated individuals.

 

Q: What is the concern about SARS-CoV-2 variants and vaccine efficacy?  

A: Viruses mutate over time; therefore, new variants of viruses tend to emerge. The majority of such mutations do not produce relevant changes to viruses, but occasionally mutations occur that may benefit the virus, including the ability to evade vaccine-induced immunity.

Since the emergence of SARS-CoV-2 in late 2019, multiple new variants of concern have emerged and begun circulating around the world (Rambaut, November 2020Tegally, April 2021; Davies, April 2021Greaney, January 2021). Some important variants of interest include:

  • Alpha, 20B/501Y.V1, or B.1.1.7 lineage, which emerged in the U.K.;
  • Beta, 20C/501Y.V2, or B.1.351 lineage, which emerged in South Africa;
  • Gamma, 20J/501Y.V3, or P.1. lineage, which emerged in Brazil and Japan;
  • Epsilon, 20C/S:452R, including the B.1.427 and B.1.429 lineages, which emerged in California;
  • Eta, B.1.526 and B.1.526.1 lineages, which emerged in New York; and
  • Delta, B.1.617, which emerged in India.

Many of these variants contain mutations that are associated with reduced neutralization by sera obtained from vaccinated individuals or reduced susceptibility to currently available monoclonal antibodies against SARS-CoV-2 spike protein. However, these observations may or may not translate into reduced vaccine clinical efficacy. Many of the COVID-19 vaccine clinical trials were conducted during time periods or in settings where variants were not circulating; therefore, much of our knowledge of their efficacy against SARS-CoV-2 variants comes from post-authorization observational studies.

 

Q: What is known about the mRNA vaccines’ clinical efficacy against SARS-CoV-2 variants?  

A: The Phase 3 trials of both the Moderna and Pfizer-BioNTech 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.

In an analysis of a mass vaccination campaign among U.K. health care workers with the Pfizer-BioNTech COVID-19 vaccine, the investigators measured the incidence of new SARS-CoV-2 infections from Dec. 8, 2020 to Feb. 5, 2021, when the B.1.1.7 variant accounted for >50% of circulating SARS-CoV-2 strains (Hall, April 2021). In this study, vaccine effectiveness was 70% (95% CI, 55-85) against SARS-CoV-2 infection (asymptomatic and symptomatic cases) starting 21 days after the first dose, and increased to 85% (95% CI, 74-96) starting 7 days after the second dose. In a separate analysis of SARS-CoV-2 cases in the U.K., investigators at Public Health England conducted a test-negative design observational study to estimate the effectiveness of the Pfizer-BioNTech COVID-19 vaccine against the B.1.617.2 variant first identified in India and noted only a small reduction in effectiveness compared with the B.1.1.7 variant (Bernal, May 2021).

In a separate study of nationwide SARS-CoV-2 surveillance data from Israel following a mass vaccination campaign with the Pfizer-BioNTech COVID-19 vaccine, vaccine effectiveness was 90.5% against symptomatic SARS-CoV-2 infection starting 7 days after dose 2. The prevalence of the B.1.1.7 variant was estimated to be 95%, based on the rate of spike gene target failure at one of the testing sites from which surveillance data were reported (Haas, May 2021).

Finally, in an analysis of the impact of a mass vaccination campaign with the Pfizer-BioNTech COVID-19 vaccine in Qatar, the investigators estimated the prevalence of the B.1.1.7 and B.1.351 variants to be 44.5% and 50% respectively. In this study, vaccine effectiveness was 89.5% against any documented infection with the B.1.1.7 variant, and 75% against any documented infection with the B.1.351 variant. Vaccine effectiveness against severe, critical or fatal SARS-CoV-2 infection due to any variant was 97.4% (Abu-Raddad, May 2021).

 

Q: What is known about the viral vector vaccines’ clinical efficacy against SARS-CoV-2 variants?  

A: There are limited real-world vaccine efficacy data for the Johnson & Johnson/Janssen COVID-19 vaccine against SARS-CoV-2 variants. The Phase 3 trial of Ad26.COV2.S was conducted in multiple countries, where new SARS-CoV-2 variants did emerge, and strain sequencing analyses of COVID-19 cases in the study are being performed. As of Feb. 12, 2021, 71.7% of cases reported in the trial had been sequenced. In subgroup analyses of vaccine efficacy against moderate to severe/critical COVID-19 by country of participation, vaccine efficacy was lower in South Africa (vaccine efficacy of 52.0%; 95% CI, 30.3-67.4) compared to the United States (vaccine efficacy of 74.4%; 95% CI, 65.0-81.6). In the United States, 96.4% of strain sequences were identified as SARS-CoV-2 Wuhan-H1 variant D614G, whereas in South Africa, 94.5% of strain sequences were identified as 20H/501Y.V2 variant (B.1.351) (Sadoff, April 2021).

The efficacy of the Oxford-AstraZeneca COVID-19 vaccine against SARS-CoV-2 variants has also been evaluated. In a post-hoc analysis of the Phase 2/3 clinical trial of ChAdOx1 conducted in the U.K., where the B.1.1.7 variant emerged in late 2020, vaccine efficacy was 70.4% against symptomatic COVID-19 due to the B.1.1.7 variant, and 81.5% against symptomatic COVID-19 due to non-B.1.1.7 variants, but this difference was not statistically significant (Emary, April 2021).

One of the Phase 3 trials of ChAdOx1 was conducted in South Africa. During that study, 41 (97.6%) of the 42 SARS-CoV-2 viruses involved in primary endpoint analyses were sequenced, of which 39 (95.1%) were the B.1.351 variant. There were 19 COVID-19 cases among ChAdOx1 recipients (15 mild, 4 moderate, 0 severe) and 23 among placebo recipients (17 mild, 6 moderate, 0 severe), giving an overall vaccine efficacy of 21.9% (95% CI, -49.9-59.8), suggesting that ChAdOx1 is not protective against the B.1.351 variant. As further evidence of this difference in efficacy, the investigators in this study conducted a post-hoc analysis of vaccine efficacy limited to cases occurring before Oct. 31, 2020 (i.e., before the B.1.351 variant emerged in South Africa). In this analysis, vaccine efficacy was determined to be 75.4% (95% CI, 8.7-95.5), similar to the reported vaccine efficacy in Phase 3 trials (Madhi, February 2021). Investigators at Public Health England also conducted a test-negative design observational study to estimate the effectiveness of the Oxford-AstraZeneca COVID-19 vaccine against the B.1.617.2 variant first identified in India and noted only a small reduction in effectiveness compared with the B.1.1.7 variant (Bernal, May 2021).

 

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

A: There are still limited data about individuals that develop SARS-CoV-2 infection after vaccination. Investigators at The Rockefeller University in New York described mild breakthrough infections in two fully vaccinated individuals with onset 19 and 36 days after the second dose of an mRNA COVID-19 vaccine (Hacisuleyman, April 2021). In this study, full genome sequencing of the viruses causing breakthrough infection revealed mutations in the spike protein. In an analysis of breakthrough SARS-CoV-2 infections reported to CDC, 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 (CDC, May 2021). These data suggest that breakthrough infections after vaccination do occur, but are rare and usually associated with mild illness or are asymptomatic.

 

Safety of COVID-19 Vaccines

Q: What were the most common adverse reactions related to the mRNA COVID-19 vaccines in clinical trials? How do these differ by age and dose?

A: The most common adverse effects reported in the Phase 3 trials of the Moderna and Pfizer-BioNTech COVID-19 vaccines included injection site pain, fatigue, headache, muscle pain, chills and joint pain (Baden, February 2021; Polack, December 2020). The rates of local and systemic adverse events following vaccination were similar between the Moderna and Pfizer-BioNTech vaccines. These adverse events were more common in younger vaccine recipients (age <65 years in the Moderna trial, and age <55 years in the Pfizer-BioNTech trial) and after the second dose of vaccine. Similar findings were observed in an analysis of reports submitted to the Vaccine Adverse Events Reporting System and v-safe, which included data on 13,794,904 doses of mRNA COVID-19 vaccines administered in the U.S. from Dec. 14, 2020 to Jan. 13, 2021 (Gee, February 2021).

More information on the safety outcomes of these vaccines is available on the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine pages of the COVID-19 Real-Time Learning Network.

 

Q: Is there any association between the mRNA COVID-19 vaccines and neurologic adverse events, including Bell’s palsy, transverse myelitis or Guillain-Barré syndrome?

A: There was a numerical imbalance in the number of cases of Bell’s palsy identified among recipients of the Pfizer-BioNTech and Moderna COVID-19 vaccines in Phase 3 clinical trials. Four participants who received the Pfizer-BioNTech vaccine later developed Bell’s palsy (compared to zero in the placebo group of that study) and three participants who received the Moderna vaccine later developed Bell’s palsy (compared to one in the placebo group of that study). Overall, this was too few cases of Bell’s palsy to establish a statistically significant association with vaccination (Ozonoff, April 2021), but surveillance is ongoing.

There have been no cases of transverse myelitis or Guillain-Barré syndrome reported following vaccination among participants in either of the mRNA COVID-19 vaccine clinical trials.

A history of any of these conditions is not a contraindication or precaution to vaccination with either mRNA COVID-19 vaccine. Any occurrence of these conditions following mRNA COVID-19 vaccination should be reported to VAERS.

 

Q: What are the frequency and characteristics of anaphylaxis or serious allergic reactions after mRNA COVID-19 vaccines? What are the risk factors for developing an allergic reaction?

A: Anaphylaxis and serious allergic reactions were not observed in the clinical trials of mRNA COVID-19 vaccines, but were recognized shortly after they were authorized for use and deployed in mass vaccination campaigns.

In two separate analyses of data submitted to the Vaccine Adverse Events Reporting System, which comprised reports from 1,893,360 first doses of the Pfizer-BioNTech COVID-19 vaccine and 4,041,396 first doses of the Moderna COVID-19 vaccine in the U.S., there were just 175 cases of possible allergic reactions after the Pfizer-BioNTech vaccine and just 108 cases of possible allergic reactions after the Moderna vaccine.

  • Of the 175 reactions reported after the Pfizer-BioNTech vaccine, only 21 (12%) met the Brighton Collaboration case definition criteria for anaphylaxis. Most of these were in women (n=19, 90%) and median time to onset of symptoms was 15 minutes. Four of the cases required hospitalization, while 17 were managed in the emergency department. Most of the cases of anaphylaxis had a documented history of allergies to drugs, foods or insect stings (n=17, 81%), and 7 (33%) had previously experienced anaphylaxis. The 83 non-anaphylaxis reactions were also predominantly in women (90%), with a 12-minute median interval to symptom onset. These reactions included pruritus, rash, itchy and scratchy sensations in the throat and mild respiratory symptoms (CDC COVID-19 Response Team, January 2021).
  • Of the 108 reactions reported after the Moderna vaccine, only 10 (9%) met the Brighton Collaboration case definition criteria for anaphylaxis. All of these were in women and median time to onset of symptoms was 7.5 minutes. Six of the cases required hospitalization (5 in the ICU, 4 of whom required intubation) and 4 were managed in the emergency department. Most (n=9, 90%) of the cases of anaphylaxis had a documented history of allergies to drugs or foods, and 5 (50%) had previously experienced anaphylaxis. There were 43 non-anaphylaxis reactions that were also predominantly in women (91%) with the median interval to symptom onset being 14 minutes. These reactions included pruritus, rash, itchy sensations in the mouth or throat, sensation of throat closure and respiratory symptoms (CDC COVID-19 Response Team, January 2021).

Finally, in a prospective study of 64,900 Mass General Brigham employees who received a first dose of a mRNA COVID-19 vaccine between Dec. 16, 2020 and Feb. 12, 2021, 1,365 (2.1%) of employees reported any allergic symptoms, and there were 16 (0.025%) employees that experienced of anaphylaxis. Rates of allergic reactions were slightly higher with the Moderna COVID-19 vaccine (2.20 vs. 1.95%, p=0.03). Nearly all (n=15, 94%) of the cases of anaphylaxis were among women, and nearly a third (n=5, 31%) had a history of anaphylaxis. One of the cases of anaphylaxis required ICU admission, 9 received IM epinephrine and all recovered without sequelae (Blumenthal, March 2021).

 

Q: What is the role of polyethylene glycol-2000 in the allergic reactions observed after mRNA COVID-19 vaccines?

A: Both of the currently authorized mRNA COVID-19 vaccines use a nanolipid particle to deliver the vaccine mRNA, and in both the Pfizer-BioNTech and Moderna COVID-19 vaccines that nanolipid particle contains a molecule called polyethylene glycol-2000. PEG is a widely used compound in medications, cosmetics and food additives and is an uncommon cause of allergy. However, rare allergic or infusion reactions to other formulations of PEG or pegylated formulations of certain medications have been described. PEG had not been included in any vaccine prior to the mRNA COVID-19 vaccines, therefore the causal link between PEG and severe allergic reactions after receipt of an mRNA COVID-19 vaccine has not been definitively established. However, a severe allergic reaction after receipt of one of the mRNA COVID-19 vaccines is considered a contraindication to the other mRNA COVID-19 vaccine.

 

Q: Which COVID-19 vaccine is recommended for an individual with a history of anaphylaxis?

A: CDC has developed recommendations for management of individuals with a history of anaphylaxis or other allergic reactions to the specific ingredients contained within the COVID-19 vaccines or to other substances.

 

Q: What were the most common adverse reactions related to the viral vector COVID-19 vaccines in clinical trials?

A: The most common adverse effects reported in the Phase 3 trial of the Johnson & Johnson/Janssen COVID-19 vaccine included injection site pain, headache, fatigue and muscle aches (Sadoff, April 2021). In a Phase 1/2 trial of the Oxford-AstraZeneca COVID-19 vaccine, the most common adverse effects were mild-moderate in severity, and most frequently included injection site pain (67%) and tenderness (83%), fatigue (70%), headache (68%) and muscle ache (60%). The frequency of these adverse events was less after the second dose of vaccine among recipients who received two doses (Folegatti, August 2020). There were 2 cases of transverse myelitis in the Phase 3 trial of the Oxford-AstraZeneca COVID-19 vaccine; 1 of these was determined to be unrelated to the vaccine, and the other was considered possibly related (Voysey, December 2020).

 

Q: In comparing the mRNA COVID-19 vaccines and the Ad26.COV2.S vaccine, which is safer and will have fewer side effects for people?

A: In the Phase 3 trial data submitted to FDA, the most common solicited adverse reactions among Ad26.COV2.S vaccinated individuals were injection site pain (48.6%), headache (38.9%), fatigue (38.2%), muscle pain (33.2%), nausea (14.2%) and fever (9.0%). These were more common in patients younger than 60 years of age. Overall, these rates were lower than those reported for both mRNA vaccines; however, all the currently authorized COVID-19 vaccines are safe.

 

Q: What are the hematologic/thrombotic adverse events that have been linked to the Johnson & Johnson/Janssen and Oxford-AstraZeneca COVID-19 vaccines?

A: In post-authorization surveillance of the Johnson & Johnson/Janssen COVID-19 vaccine, a small number (n=6) of rare thrombotic events — cerebral venous sinus thrombosis — associated with thrombocytopenia were identified among vaccine recipients based on data reported to VAERS. This led to a brief pause in the use of this vaccine on April 13, 2021 and a review of safety data by CDC’s Advisory Committee on Immunization Practices on April 23, 2021. In this review, 15 total cases of thrombosis with thrombocytopenia syndrome were identified, including 12 cases of CVST. All the TTS cases occurred among women, and 13 of 15 were in women aged 18-49 years old. The median age of the case patients was 37 years, and the median interval from vaccination to symptom onset was 8 days (range, 6−15 days) (MacNeil, April 2021). There was one case of CVST with thrombocytopenia in a male during the Phase 3 trial of Ad26.COV2.S (Sadoff, April 2021).

The Oxford-AstraZeneca COVID-19 vaccine has been associated with both arterial and venous thrombotic events. In an analysis of data reported to EudraVigilance (a drug safety reporting system for the European Union), the European Medicines Agency identified 169 cases of CSVT and 53 cases of splanchnic vein thrombosis following receipt of the Oxford-AstraZeneca COVID-19 vaccine (out of more than 34 million doses administered). These thrombotic events occurred concurrently with thrombocytopenia, usually within 2 weeks of receipt of the vaccine, and mostly among women under age 60. Subsequently, three independent case series from Norway (Schultz, April 2021), Germany/Austria (Greinacher, April 2021) and the United Kingdom (Scully, April 2021) described a total of 39 patients (27 women, 12 men) with venous thromboses associated with thrombocytopenia that occurred within 4 weeks (range 5-24 days) after vaccination with the Oxford-AstraZeneca COVID-19 vaccine. Given the resemblance of this syndrome to heparin-induced thrombocytopenia, in two of these studies the investigators tested case patients for anti-platelet factor 4 antibodies and found elevated titers in the majority of patients, leading them to propose a new syndrome called vaccine-induced thrombotic thrombocytopenia.

 

Q: What is vaccine-induced thrombotic thrombocytopenia, and what is the hypothesized mechanism?

A: Vaccine-induced thrombotic thrombocytopenia is a syndrome characterized by venous or arterial thrombosis associated with thrombocytopenia and detectable anti-platelet factor 4 antibodies that occurs within 3 weeks after receipt of either the Oxford-AstraZeneca or Johnson & Johnson/Janssen COVID-19 vaccine. The American Society of Hematology has developed a case definition with recommendations for diagnostic evaluation and management of patients with suspected VITT.

 

Q: What are the long-term safety implications of the vaccines?

A: In all the COVID-19 vaccine trials, the rate of serious adverse events was low. Additional data on long-term safety will be available with more time and as more individuals get vaccinated. Adverse events that occur in an individual following COVID-19 vaccination will be reported to VAERS. Furthermore, CDC has developed a voluntary smartphone-based tool, called v-safe, which uses text messaging and web surveys to provide near real-time health check-ins after patients receive COVID-19 vaccination. 

 

COVID-19 Vaccination by Patient Population

 

Q: Are there any special considerations for COVID-19 vaccination based on age or biological sex?

A: Each of the COVID-19 vaccines has different age restrictions.

  • The Pfizer-BioNTech COVID-19 vaccine is authorized for use in individuals aged 12 and older;
  • The Moderna COVID-19 vaccine is authorized for use in individuals aged 18 and older;
  • The Johnson & Johnson/Janssen COVID-19 vaccine is authorized for use in individuals aged 18 and older.

All these vaccines have been demonstrated to be similarly efficacious across different age groups and biological sexes. From a safety perspective, in general older individuals experienced lower rates of adverse effects related to the vaccine compared with younger individuals.

The Johnson & Johnson/Janssen COVID-19 vaccine FDA Fact Sheets were updated to include information about thrombotic thrombocytopenia syndrome whose incidence is higher among women aged 18-49 years.

 

Q: For racial/ethnic populations who were less well represented in the COVID-19 vaccine studies, how do we know if the vaccines are equally safe and efficacious?

A: All the COVID-19 vaccine Phase 3 trials included individuals from diverse racial/ethnic groups. There were no specific safety signals related to any of the vaccines by racial/ethnic group. There were too few cases in the subgroup of each of these populations to determine a robust point estimate for efficacy stratified by racial/ethnic group. Overall, there were no significant differences in efficacy for each of the vaccines between these groups.

More information on the patient populations included in the clinical trials of these vaccines is available on our vaccine-platform-specific pages.  

 

Q: What is the efficacy of the vaccines in those with comorbidities, such as obesity, hypertension, chronic kidney disease, diabetes or chronic heart and lung disease?

A: All the COVID-19 vaccine Phase 3 trials included individuals with co-morbidities associated with an increased risk for severe COVID-19. In the analyses of the Pfizer-BioNTech, Moderna and Johnson & Johnson/Janssen COVID-19 vaccine trials, these individuals were pooled together for vaccine efficacy calculations because there were too few cases in the subgroup of patients with each comorbidity to determine a robust point estimate stratified by individual condition. Overall, there were no significant differences in efficacy for each of the vaccines between individuals with “any comorbidity” and those with no comorbidities.

 

Q: What is known about the safety of the COVID-19 vaccines in pregnant or lactating individuals?

A: Pregnant people were excluded from the pre-authorization studies of all the COVID-19 vaccines. A small number of pregnancies did occur during the Phase 3 trials (23 in the Pfizer-BioNTech trial, 13 in the Moderna trial and 8 in the Johnson & Johnson/Janssen trial), but too few to draw any meaningful conclusions about safety. Thus, our knowledge of the safety of COVID-19 vaccines in pregnancy comes from post-authorization studies.

In an analysis of safety data collected through v-safe and VAERS (Shimabukuro, April 2021), investigators found 35,691 individuals who were identified as pregnant (30,887 or 86.5% were pregnant at the time of vaccination) and who had received a COVID-19 vaccine between Dec. 14, 2020 and Feb. 28, 2021. During this time, only the Pfizer-BioNTech and Moderna COVID-19 vaccines were authorized for emergency use in the U.S. Overall, local and systemic reactogenicity events occurred at a similar rate between pregnant and non-pregnant women.

The authors also analyzed the v-safe pregnancy registry, which included data from 3,958 pregnant people who had received a COVID-19 vaccine. Of these, nearly all (>98%) were between age 25-44 years, 2,136 (54%) had received the Pfizer-BioNTech COVID-19 vaccine and 1,822 (46%) had received the Moderna COVID-19 vaccine; additionally, 1,132 (28.6%) received their first dose of vaccine in the first trimester, 1,714 (43.3%) received it in the second trimester, and 1,019 (25.7%) received it in the third trimester. There were 827 individuals who completed their pregnancy during this time period, of whom 712 individuals delivered 724 live-born infants; of these 9.4% were born preterm, 3.2% were small for gestational age, and 2.2% had major congenital anomalies. These rates were similar to those reported for pregnancies prior to the pandemic; thus, no safety signal was identified for the mRNA COVID-19 vaccines in pregnancy.

No clinical safety data specific to the Johnson & Johnson/Janssen COVID-19 vaccine have been published, and the Phase 3 trial of Ad26.COV2.S excluded individuals who were pregnant at the time of screening or planned to become pregnant within 3 months of vaccination. Only 8 pregnancies occurred during the conduct of that study through Jan. 22, 2021 (4 in the vaccine group, 4 in the placebo group), thus no conclusions about safety can be drawn.

The Pfizer-BioNTech, Moderna and Johnson & Johnson/Janssen COVID-19 vaccine EUAs do not exclude pregnant or lactating individuals. Per CDC ACIP recommendations, people who are pregnant or breastfeeding may choose to be vaccinated with any of these vaccines. There is no recommendation for routine pregnancy testing before receipt of a COVID-19 vaccine. Those who are trying to become pregnant do not need to avoid pregnancy after COVID-19 vaccination. The EUA for the Johnson & Johnson/Janssen vaccine has been updated to include information about the risk of thrombosis with thrombocytopenia syndrome in women under age 50 (who are of childbearing age).

The American College of Obstetricians and Gynecologists maintains updated recommendations regarding COVID-19 vaccination in pregnant and lactating individuals.

 

Q: What is known about the efficacy of the COVID-19 vaccines in pregnant individuals?

A: Observational data indicate that pregnant people may be at risk for more severe illness and worse outcomes from COVID-19. Additionally, they may be at an increased risk of adverse pregnancy outcomes, such as preterm labor. As such, pregnant individuals are a high-priority group for vaccination against COVID-19. However, to date, there are no vaccine efficacy data specific to pregnant people available for any of the COVID-19 vaccines, though immune responses to mRNA COVID-19 vaccines in pregnant people have been evaluated.

In a prospective immunogenicity study of 131 women (84 pregnant, 31 lactating and 16 non-pregnant) (Gray, March 2021), investigators assessed anti-SARS-CoV-2 spike and receptor binding domain antibody responses following vaccination with one of the mRNA COVID-19 vaccines. Antibodies were measured prior to vaccination and after vaccination at the time of the second dose of vaccine, and 2-6 weeks after the second dose. Of the 13 pregnant women who delivered during the study, 10 also provided specimens at delivery (umbilical cord blood), and lactating women also provided breastmilk specimens for antibody measurements. All vaccinated participants demonstrated a robust antibody response following vaccination, and there were no differences in the IgG, IgM or IgA response between pregnant, lactating and non-pregnant women; antibody concentrations after vaccination in all the groups were greater than those detected in banked sera from pregnant women with natural SARS-CoV-2 infection in the preceding 4-12 weeks. Anti-SARS-CoV-2 spike and receptor binding domain antibodies were detectable in breast milk (among lactating women who received vaccine) and in umbilical cord blood (among pregnant women who received vaccine). Transplacental transfer of IgG was greatest for those women vaccinated earlier in pregnancy.

 

Q: Can the COVID-19 vaccines make people of child-bearing age infertile?

A: No. There is no evidence linking any of the COVID-19 vaccines to infertility. This myth arose as a result of misinformation circulated on the internet regarding the antigen created by these vaccines (the SARS-CoV-2 spike protein) and its supposed similarity to a protein important for placental attachment (syncytin-1). None of the COVID-19 vaccines contain syncytin-1, nor does the genetic material used in the vaccines encode for syncytin-1. Furthermore, the SARS-CoV-2 spike protein that is generated as a result of vaccination with the currently available COVID-19 vaccines has no structural similarity to syncytin-1, and no data indicate that the antibodies formed as a result of COVID-19 vaccination target syncytin-1.

 

Q: What is known about the safety of COVID-19 vaccines in immunocompromised hosts, e.g., people with HIV, people who have received organ or stem cell transplants, people receiving chemotherapy for cancers or people receiving chronic immunosuppressive therapy for autoimmune and other disorders?

A: The theoretical risks of vaccination (of any kind, not just COVID-19 vaccines) in immunocompromised individuals fall into two main categories: 1) the risk associated with live virus vaccines, or 2) the risk of exacerbating an immunologically-driven process (e.g., an autoimmune disease or organ rejection) as a result of the immune activation generated by the vaccine.

Immunocompromised individuals were mostly excluded from the pre-authorization studies of the currently available COVID-19 vaccines; therefore, there are only limited safety data about these vaccines in these patient populations. However, none of the currently available COVID-19 vaccines are live virus vaccines; the viral vector vaccines are replication-deficient (or replication incompetent), meaning the viral vector used to deliver the SARS-CoV-2 genetic material does not have the capability for self-replication and transmission to other cells or other individuals. Thus, in terms of the theoretical risks associated with live virus vaccines, there is no risk to immunocompromised individuals associated with the currently authorized COVID-19 vaccines. Additionally, to date, there have been no data — either from clinical trials or from post-authorization observational studies — to suggest an elevated risk of autoimmune or inflammatory conditions among COVID-19 vaccine recipients.

 

Q: Is the vaccine safe for transplant patients?

A: Immunocompromised people may be at risk for severe COVID-19; therefore, CDC states these groups may receive the vaccine if there are no contraindications. Transplant recipients should be counseled that the effectiveness and safety profile of these vaccines for them are not currently known. However, as these are not live virus vaccines, it is unlikely that these vaccines would pose a safety risk. It is important for there to be intact host immunity in individuals receiving the vaccine for there to be optimal protective immunity post-vaccination, especially with respect to antigen presentation, B and T cell activation and plasma B cell antibody generation. Therefore, individuals lacking functional adaptive immune cells may be unable to generate a fully protective immune response to the SARS-CoV-2 vaccine. Therefore, transplant recipients should be advised regarding the importance of maintaining all current guidance to protect themselves even after vaccination. Additionally, caregivers and household contacts should be strongly encouraged to get vaccinated when vaccine is available in an effort to protect the patient.

 

Q: Are there any considerations regarding COVID vaccination in oncology patients, many of whom are immunocompromised either by virtue of their disease of cancer or their treatment, e.g., chemotherapy, radiation, stem cell transplant? Do we think it will be safe and efficacious in this group?

A: Persons with HIV infection or other immunocompromising conditions, or who take immunosuppressive medications or therapies, might be at increased risk for severe COVID-19. Data are not currently available to establish vaccine safety and efficacy in these groups. Persons with stable HIV infection were included in mRNA COVID-19 vaccine clinical trials, though data remain limited. Immunocompromised individuals may receive COVID-19 vaccination if they have no contraindications to vaccination. However, they should be counseled about the unknown vaccine safety profile and effectiveness in immunocompromised populations, as well as the potential for reduced immune responses and the need to continue to follow all current guidance to protect themselves against COVID-19.  

Oncology patients should be counseled that the effectiveness and safety profile of these vaccines for them are limited. As these are not live virus vaccines, it is unlikely that these vaccines would pose a safety risk. It is important for there to be intact host immunity in individuals receiving the vaccine for there to be optimal protective immunity post-vaccination, especially with respect to antigen presentation, B and T cell activation and plasma B cell antibody generation. Therefore, individuals lacking functional adaptive immune cells may be unable to generate a fully protective immune response to the SARS-CoV-2 vaccine. Therefore, patients with cancer should be advised regarding the importance of maintaining all current guidance to protect themselves even after vaccination. Additionally, caregivers and household contacts should be strongly encouraged to get vaccinated when vaccine is available in an effort to protect the patient.

 

Q: Can patients with autoimmune diseases receive the vaccines? Is there concern for triggering autoimmune diseases/responses in susceptible individuals?

A: Autoimmune disease is not a contraindication for the mRNA vaccines. The study populations for both mRNA vaccine trials included participants with autoimmune disease. No imbalances were observed in the occurrence of symptoms consistent with autoimmune conditions or inflammatory disorders in clinical trial participants who received an mRNA COVID-19 vaccine compared to placebo.  

 

Q: Are there any plans to do Phase 4 studies in immunocompromised hosts — such as people with transplants, people chronically immunosuppressed for autoimmune disorders or people with HIV?

A: The FDA EUA recommends that immunocompromised individuals and other subpopulations with specific comorbidities be studied in post-authorization observational studies. People with HIV were included in both the Pfizer-BioNTech and Moderna trials, although their numbers were low.

 

Q: Can the vaccine be administered to asplenic patients — either those with functional asplenia or post splenectomy?

A: For both mRNA vaccines, CDC recommends that groups at high risk for severe illness (including those with sickle cell disease who have functional asplenia) may still receive the vaccine if there are no contraindications. It is important for there to be intact host immunity in individuals receiving the vaccine for there to be optimal protective immunity post-vaccination, especially with respect to antigen presentation, B and T cell activation and plasma B cell antibody generation. Therefore, individuals lacking functional adaptive immune cells, such as those who are asplenic, may be unable to generate a fully protective immune response to the SARS-CoV-2 vaccine. Therefore, they should be advised regarding the importance of maintaining all current guidance to protect themselves even after vaccination. Additionally, caregivers and household contacts should be strongly encouraged to get vaccinated when vaccine is available in an effort to protect the patient.

 

Q: In patients with HIV, are there any recommendations for getting the vaccine in patients based on CD4 count and viral suppression?  

A: Individuals with well-controlled HIV were included in the mRNA vaccine trials; however, the number was small. Therefore, there are insufficient data to establish efficacy and safety in this group. Because people with HIV may be at risk for severe COVID-19, CDC recommends this group may still receive the vaccine if there are no contraindications. People with HIV, particularly those with low CD4 counts or who are not on HAART, should be counseled that they may have a weakened immune response when compared to the general population, and thus should be advised regarding the importance of maintaining all current guidance to protect themselves even after vaccination. Additionally, caregivers and household contacts should be strongly encouraged to get vaccinated when the vaccine is available in an effort to protect the patient.  

 

Q: In the Johnson & Johnson/Janssen COVID-19 vaccine trial, what was the vaccine efficacy in HIV patients? What are the implications?

A: The Phase 3 trial of Ad26.COV2.S included 1,218 individuals with HIV, which constituted 2.8% of the total study population. There were too few outcomes among this subgroup to draw any meaningful conclusions about vaccine efficacy. Specifically, there were 5 cases of moderate to severe/critical COVID-19 in both the vaccine and placebo group starting at least 14 days after vaccination, and 2 cases in the vaccine group and 4 in the placebo group starting at least 28 days after vaccination. Safety and immunogenicity studies in immunocompromised individuals are planned, but details of these studies are not yet available.

 

Q: Are there any concurrent medications that are uniquely contraindicated in recipients of mRNA vaccines? Will patients need to stop any medications prior to vaccination?

A: There are currently no medications that are contraindicated in individuals receiving mRNA vaccines. Due to lack of data on safety and efficacy of the vaccine administered simultaneously with other vaccines, mRNA COVID-19 vaccines should be administered alone with a minimum interval of 14 days before or after administration of any other vaccines.

Based on the estimated half-life of monoclonal antibodies or convalescent plasma as well as evidence suggesting that reinfection is uncommon in the 90 days after initial infection, vaccination should be deferred for at least 90 days as a precautionary measure until additional information becomes available, to avoid interference of the antibody treatment with vaccine-induced immune responses.

 

Q: What concomitant medications or diseases may inhibit or prevent the vaccine from inducing immune response?

A: According to the American Society of Hematology and the American Society for Transplantation and Cellular Therapy, the following immunocompromised patient populations could have attenuated or absent response to SARS-CoV-2 vaccines (this list is not comprehensive):

  • “Primary and secondary immunodeficiencies involving adaptive immunity;
  • Splenectomy or functional asplenia (e.g., sickle cell disease);
  • B cell directed therapies (e.g., blocking monoclonal antibodies against CD20 or CD22, bispecific agents like blinatumomab, CD19 or CD22-directed CAR-T cell therapies, BTK inhibitors);
  • T cell directed therapies (e.g., calcineurin inhibitors, antithymocyte globulin, alemtuzumab);
  • Many chemotherapy regimens;
  • High-dose corticosteroids (20 mg per dose or >2 mg/kg/day daily prednisone or equivalent);
  • Hematopoietic cell transplantation, especially within the first 3-6 months after autologous HCT and often longer after allogeneic HCT;
  • Underlying aberrant immunity (e.g., graft-vs.-host disease, graft rejection, absent or incomplete immune reconstitution, neutropenia, lymphopenia).”

 

Q: Should an individual receiving a COVID-19 vaccination abstain from steroid use, and if so, for how long?

A: Per the American Society of Hematology and the American Society for Transplantation and Cellular Therapy, high-dose corticosteroids (20 mg per dose or >2 mg/kg/day daily prednisone or equivalent) may attenuate the immune response in individuals receiving the vaccine if they are already immunosuppressed. Doses lower than this are unlikely to significantly affect the immune response to a COVID-19 vaccine.

 

COVID-19 Vaccine Practical Considerations

 

Q: Is an informed consent form needed prior to vaccinating individuals?

A: FDA has issued an Emergency Use Authorization for the Pfizer-BioNTech, Moderna and Johnson & Johnson/Janssen COVID-19 vaccines. Vaccines received under this authorization mechanism do not require the same informed consent as one received through a clinical trial. However, before vaccination, vaccine administrators must complete the following:

  • Communicate to the recipient or their caregiver information consistent with the “Fact Sheet for Recipients and Caregivers” for the vaccine being administered (and provide a copy or direct the individual to the online fact sheet).
  • Provide pre-administration counseling that includes the following information:
    • FDA has authorized the emergency use of the vaccine, which is not an FDA-approved vaccine.
    • The recipient or their caregiver has the option to accept or refuse COVID-19 vaccine.
    • The significant known and potential risks and benefits of vaccine, and the extent to which such risks and benefits are unknown, including expected systemic and local reactogenicity and any special population-specific considerations (e.g., pregnant or lactating people, immunosuppressed persons).
    • Information about available alternative vaccines and the risks and benefits of those alternatives.
  • Provide a vaccination card to the recipient or their caregiver with the date when the recipient needs to return for the second dose of COVID-19 vaccine (the latter is only applicable to two-dose vaccines).
  • Log the vaccination information in the state/local jurisdiction’s Immunization Information System or other designated system.

 

Q: How should we counsel patients about taking acetaminophen or non-steroidal anti-inflammatory drugs to prevent or treat vaccine-associated local or systemic adverse effects?

A: Routine prophylactic administration of these medications for the purpose of preventing post-vaccination symptoms is not currently recommended, as information on the impact of this on both the immune response to the vaccine and on post-vaccine symptoms is not currently available. Per CDC, acetaminophen or NSAIDs may be taken for the treatment of post-vaccination local or systemic symptoms. In those that are pregnant, acetaminophen is preferred.

 

Q: What are the recommendations regarding co-administration of other non-COVID-19 vaccines at the same time as or closely spaced with COVID-19 vaccines?

A: Per CDC recommendations, COVID-19 vaccines can be administered with regard to timing of other vaccines. Of note, the effect of co-administration or closely spaced administration of COVID-19 and non-COVID-19 vaccines on reactogenicity has not yet been well characterized.

 

Q: How should early, late or missed doses of vaccine be managed? What if an individual experiences an adverse reaction to the first dose of a two-dose COVID-19 vaccine?

A: CDC maintains up-to-date recommendations about COVID-19 vaccine administration. The Pfizer-BioNTech and Moderna COVID-19 vaccines are two-dose vaccines, whereas the Johnson & Johnson/Janssen COVID-19 vaccine is a single dose. The recommended interval between the two doses of the mRNA COVID-19 vaccines are as follows:

  • Pfizer-BioNTech COVID-19 vaccine – dose 2 should be given 21 days (3 weeks) after dose 1
  • Moderna COVID-19 vaccine – dose 2 should be given 28 days (4 weeks) after dose 1

In general, if an individual receives two doses of an mRNA vaccine, there is no need to repeat the series and the individual should be considered fully vaccinated starting 14 days after the second dose. If the second dose is missed or delayed for any reason, it should be scheduled at the earliest opportunity.

In limited exceptional circumstances where an individual cannot be administered the same mRNA vaccine product for their second dose as they received for their first — either because it is not available or because the identity of the first dose is unknown — any available mRNA vaccine product can be administered at a minimum interval of 28 days after the individual’s first dose. If this occurs, this is considered an administration error that should be reported to VAERS.

Finally, in limited situations where an individual develops an adverse reaction to the first dose of an mRNA vaccine that is considered a contraindication to the second dose (with the same or a different mRNA vaccine), the Johnson & Johnson/Janssen COVID-19 vaccine can be administered at a minimum interval of 28 days after the first dose of the mRNA vaccine. This individual should be considered fully vaccinated with the Johnson & Johnson/Janssen COVID-19 vaccine starting 14 days after the dose.

 

Q: What is the new smartphone-based tool called v-safe?

A: When someone receives a COVID-19 vaccine, they should also receive a v-safe information sheet telling them how to enroll in v-safe. The v-safe app is now available for download, and information is available on the CDC website. If the participant enrolls, they will receive regular text messages directing them to surveys where they can report any problems or adverse reactions after receiving a COVID-19 vaccine.

 

Q: Why is it necessary to vaccinate people who have had COVID-19?

A: Given that we do not know how long immunity after COVID-19 infection lasts (notably, reinfection cases have happened 3 months following COVID-19 infection), and given people have variable immune responses after having COVID-19 (some data suggest people with mild cases may have a less robust immune response than those with severe disease), CDC recommends offering vaccination to individuals regardless of history of prior symptomatic or asymptomatic SARS-CoV-2 infection. Viral testing to assess for acute SARS-CoV-2 infection or serologic testing to assess for prior infection solely for the purpose of vaccine decision-making is not recommended. Vaccination of individuals with known current SARS-CoV-2 infection should be deferred until they have recovered from the acute illness (if they had symptoms) and criteria have been met for them to discontinue isolation.

 

Q: What advantage does getting vaccinated provide if masks are beneficial in decreasing transmission?

A: Vaccination is intended to prevent illness by providing immunity to the SARS-CoV-2 virus and may also reduce transmission of virus; in contrast, masks are only intended to reduce transmission but do not provide immunity. CDC has provided recommendations regarding the activities that fully vaccinated individuals can participate in with or without masks.

 

Q: If someone has a history of COVID-19, are they more likely to experience a side effect from a COVID-19 vaccine?

A: Large-scale data on side effects in this particular group are not yet available. All of the currently available COVID-19 vaccines have been demonstrated to be safe in patients with a prior history of documented SARS-CoV-2 infection (whether asymptomatic or symptomatic). In an immunogenicity study of 110 individuals with and without prior SARS-CoV-2 infection who received an mRNA COVID-19 vaccine, participants who were seropositive at baseline did experience more systemic adverse events associated with vaccination compared with those who were seronegative at baseline, but there were no serious adverse events reported in either group (Krammer, April 2021).

 

Q: Are there any data concerning vaccine administration during PCR- and/or symptom-diagnosed SARS-CoV-2 infection?

A: Vaccination of persons with known current SARS-CoV-2 infection should be deferred until they have recovered from the acute illness (if they had symptoms) and criteria have been met for them to discontinue isolation. This recommendation applies to persons who develop SARS-CoV-2 infection before receiving any vaccine doses as well as those who develop SARS-CoV-2 infection after the first dose but before receipt of the second dose.

 

Q: If a fully or partially vaccinated individual develops COVID-19, should their infection be managed differently than an unvaccinated individual?

A: There are limited data on breakthrough SARS-CoV-2 infections after vaccination. Based on current knowledge, prior receipt of a COVID-19 vaccine should not affect treatment decisions (including use of monoclonal antibodies, convalescent plasma, antiviral treatment or corticosteroid administration) or timing of such treatments.

 

Q: How does prior receipt of antivirals (such as remdesivir), convalescent plasma or monoclonal antibodies against SARS-CoV-2 impact the choice and timing of COVID-19 vaccination?

A: Prior receipt of antiviral therapy for SARS-CoV-2 infection should not impact vaccination decisions, including viral vector vaccines. There are no data on the safety and efficacy of COVID-19 vaccines in persons who received convalescent plasma or anti-SARS-CoV-2 monoclonal antibodies as part of COVID-19 treatment. Based on the estimated half-life of such therapies as well as evidence suggesting that reinfection is uncommon in the first 90 days after initial infection, vaccination should be deferred for at least 90 days after receipt of those products as a precautionary measure to avoid interference of the antibody treatment with vaccine-induced immune responses. This recommendation does not apply to non-SARS-CoV-2-specific immunoglobulin therapies, such as intravenous or intramuscular immunoglobulin or RhoGAM, given for other indications.

 

Q: Do COVID-19 vaccines affect the performance of SARS-CoV-2 diagnostic tests?  

A: Receipt of a COVID-19 vaccine will not affect the result of PCR or antigen-based tests for SARS-CoV-2 infection. Antibody-based tests may or may not be affected by prior COVID-19 vaccination depending on the type of assay being used. Assays that measure IgM or IgG antibodies against SARS-CoV-2 nucleocapsid protein will not be affected by currently authorized COVID-19 vaccines because the vaccine does not contain or encode the nucleocapsid protein. Assays that measure antibodies against SARS-CoV-2 spike protein may be variably affected by prior vaccination; however, none of the currently available anti-spike antibody assays is authorized for assessing post-vaccination immunity.

 

Q: Are there recommendations to test for antibodies to the vaccine after administration?

A: No. At this time antibody testing is not recommended to assess for immunity to COVID-19 following vaccination with any COVID-19 vaccine. A correlate of protection against SARS-CoV-2 infection has not been definitively established; therefore, the results of antibody testing following vaccination should not be used to make vaccination decisions.

 

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