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Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.1 Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.2-4
In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”
SIDEBAR
COVID-19 vaccination resources
Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States
Centers for Disease Control and Prevention
www.cdc.gov/vaccines/covid-19/clinical-considerations/interimconsiderations-us.html
COVID-19 ACIP vaccine recommendations
Advisory Committee on Immunization Practices (ACIP)
www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html
MMWR COVID-19 reports
Morbidity and Mortality Weekly Report
www.cdc.gov/mmwr/Novel_Coronavirus_Reports.html
A literature hub for tracking up-to-date scientific information about the 2019 novel coronavirus
National Center for Biotechnology Information of the National Library of Medicine
www.ncbi.nlm.nih.gov/research/coronavirus
Understanding COVID-19 vaccines
National Institutes of Health COVID-19 Research
https://covid19.nih.gov/treatments-and-vaccines/covid-19-vaccines
How COVID-19 affects pregnancy
National Institutes of Health COVID-19 Research
SARS-CoV-2 virology
As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.7
After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.5 The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.
Basic mRNA vaccine immunology
Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.8
mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.
mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:
- They are nonreplicating.
- They do not integrate into the host genome.
- They are highly effective.
- They can produce antibody and cellular immunity.
- They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.
Continue to: Vaccines against SARS-CoV-2
Vaccines against SARS-CoV-2
Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).9
Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)
The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.
The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.
Efficacy of COVID-19 vaccines
The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.10 This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-confirmed COVID-19 at 3-month follow-up.10 Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.
Continue to: Data from trials...
Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.17
Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.18 During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.19
In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.16 A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.20 The efficacy of the vaccines is summarized in TABLE 1.21-24
Even in patients who have natural infection, several studies have shown that COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.
Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.29
Continue to: Vaccine adverse effects
Vaccine adverse effects: Common, rare, myths
Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 121-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.a
Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.30,31
Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.
A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.33 Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.34 In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.34
A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.35 Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.
Continue to: There is emerging evidence...
There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.36 That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.
TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.36 The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.36) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations36 (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).
Myths surrounding vaccination
Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).37 There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.38
Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.39 No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.40,41
Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.8
Continue to: Boosters and vaccine mix-and-match
Boosters and vaccine mix-and-match
As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.42 There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.42 Five patients were hospitalized; none died.42 A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.
Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.43 Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.
Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.49
Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity50 (TABLE 251).
Vaccination in special populations
Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”
Continue to: Pregnant patients
Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.52 CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.53
A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from COVID-19 vaccination.54 Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.
Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.55
Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.56 In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.57
Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:
- the absence of comorbidities often seen in adults
- evidence that pediatric patients might have reduced expression of ACE-2
- a more active T-cell response in infected children, due to an active thymus.56
Continue to: Although the number of children affected...
Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.58 The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.58 Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.59,60
Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.61 Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.62 Antibody response to vaccination was also less robust in this group.
There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.63 Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.b
Predictions (or, why is a COVID-19 vaccine important?)
What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.64 First, only relative immunity is produced after infection with a seasonal coronavirus.64 Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.65 Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.
The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.66 During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.
Continue to: At approximately that time...
At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.57 In view of warning signs from wastewater surveillance, priorities for vaccination should be to:
- increase uptake in the hesitant
- get boosters to the eligible
- prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.
As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.
awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html
b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.
CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]
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3. Lurie N, Saville M, Hatchett R, et al. Developing Covid-19 vaccines at pandemic speed. N Engl J Med. 2020;382:1969-1973. doi: 10.1056/NEJMp2005630
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9. National Center for Immunization and Respiratory Diseases. Use of COVID-19 vaccines in the United States: interim clinical considerations. Centers for Disease Control and Prevention. Updated August 22, 2022. Accessed August 27, 2022. www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html#references
10. Polack FP, Thomas SJ, Kitchin N, et al; . Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603-2615. doi: 10.1056/NEJMoa2034577
11. Heinz FX, Stiasny K. Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action. NPJ Vaccines. 2021;6:104. doi: 10.1038/s41541-021-00369-6
12. Baden LR, El Sahly HM, Essink B, et al; COVE Study Group. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384:403-416. doi: 10.1056/NEJMoa2035389
13. Keech C, Albert G, Cho I, et al. Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med. 2020;383:2320-2332. doi: 10.1056/NEJMoa2026920
14. Heath PT, Galiza EP, Baxter DN, et al; . Safety and efficacy of NVX-CoV2373 Covid-19 vaccine. N Engl J Med. 2021;385:1172-1183. doi: 10.1056/NEJMoa2107659
15. Rinott E, Youngster I, Lewis YE. Reduction in COVID-19 patients requiring mechanical ventilation following implementation of a national COVID-19 vaccination program—Israel, December 2020–February 2021. MMWR Morb Mortal Wkly Rep. 2021;70:326-328. doi: 10.15585/mmwr.mm7009e3
16. Tenforde MW, Self WH, Gaglani M, et al; IVY Network. Effectiveness of mRNA vaccination in preventing COVID-19-associated invasive mechanical ventilation and death—United States, March 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:459-465. doi: 10.15585/mmwr.mm7112e1
17. Moline HL, Whitaker M, Deng L, et al. Effectiveness of COVID-19 vaccines in preventing hospitalization among adults aged ≥ 65 years—COVID-NET, 13 States, February–April 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1088-1093. doi: 10.15585/mmwr.mm7032e
18. Tenforde MW, Olson SM, Self WH, et al; ; . Effectiveness of Pfizer-BioNTech and Moderna vaccines against COVID-19 among hospitalized adults aged ≥ 65 years—United States, January–March 2021. MMWR Morb Mortal Wkly Rep. 2021;70:674-679. doi: 10.15585/mmwr.mm7018e1
19. Johnson AG, Amin AB, Ali AR, et al. COVID-19 incidence and death rates among unvaccinated and fully vaccinated adults with and without booster doses during periods of Delta and Omicron variant emergence—25 U.S. jurisdictions, April 4–December 25, 2021. MMWR Morb Mortal Wkly Rep. 2022;71:132-138. doi: 10.15585/mmwr.mm7104e2
20. Kim Y-E, Huh K, Park Y-J, et al. Association between vaccination and acute myocardial infarction and ischemic stroke after COVID-19 infection. JAMA. Published online July 22, 2022. doi: 10.1001/jama.2022.12992
21. Centers for Disease Control and Prevention. Pfizer-BioNTech COVID-19 vaccine reactions & adverse events. Updated June 21, 2022. Accessed September 9, 2022. www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/reactogenicity.html
22. Centers for Disease Control and Prevention. The Moderna COVID-19 vaccine’s local reactions, systemic reactions, adverse events, and serious adverse events. Updated June 21, 2022. Accessed September 9, 2022. www.cdc.gov/vaccines/covid-19/info-by-product/moderna/reactogenicity.html
23. Centers for Disease Control and Prevention. The Janssen COVID-19 vaccine’s local Reactions, Systemic reactions, adverse events, and serious adverse events. Updated August 12, 2021. Accessed September 9, 2022. www.cdc.gov/vaccines/covid-19/info-by-product/janssen/reactogenicity.html
24. Centers for Disease Control and Prevention. Novavax COVID-19 vaccine local reactions, systemic reactions, adverse events, and serious adverse events. Updated August 31, 2022. Accessed September 9, 2022. www.cdc.gov/vaccines/covid-19/info-by-product/novavax/reactogenicity.html
25. Greaney AJ, Loes AN, Gentles LE, et al. Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Sci Transl Med. 2021;13:eabi9915. doi: 10.1126/scitranslmed.abi9915
26. Hall V, Foulkes S, Insalata F, et al. Protection against SARS-CoV-2 after Covid-19 vaccination and previous infection. N Engl J Med. 2022;386:1207-1220. doi: 10.1056/NEJMoa2118691
27. Klompas M. Understanding breakthrough infections following mRNA SARS-CoV-2 avccination. JAMA. 2021;326:2018-2020. doi: 10.1001/jama.2021.19063
28. Kustin T, Harel N, Finkel U, et al. Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Nat Med. 2021;27:1379-1384. doi: 10.1038/s41591-021-01413-7
29. Yu Y, Esposito D, Kang Z, et al. mRNA vaccine-induced antibodies more effective than natural immunity in neutralizing SARS-CoV-2 and its high affinity variants. Sci Rep. 2022;12:2628. doi: 10.1038/s41598-022-06629-2
30. Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices—United States, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70:977-982. doi: 10.15585/mmwr.mm7027e2
31. MacNeil JR, Su JR, Broder KR, et al. Updated recommendations from the Advisory Committee on Immunization Practices for use of the Janssen (Johnson & Johnson) COVID-19 vaccine after reports of thrombosis with thrombocytopenia syndrome among vaccine recipients—United States, April 2021. MMWR Morb Mortal Wkly Rep. 2021;70:651-656. doi: 10.15585/mmwr.mm7017e4
32. Patone M, Mei XW, Handunnetthi L, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med. 2022;28:410-422. doi: 10.1038/s41591-021-01630-0
33. Boehmer TK, Kompaniyets L, Lavery AM, et al. Association between COVID-19 and myocarditis using hospital-based administrative data—United States, March 2020–January 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1228-1232. doi: 10.15585/mmwr.mm7035e5
34. Block JP, Boehmer TK, Forrest CB, et al. Cardiac complications after SARS-CoV-2 infection and mRNA COVID-19 vaccination—PCORnet, United States, January 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:517-523. doi: 10.15585/mmwr.mm7114e1
35. Rosemblum H. COVID-19 vaccines in adults: benefit–risk discussion. Centers for Disease Control and Prevention. July 22, 2021. Accessed September 21, 2022. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/05-COVID-Rosenblum-508.pdf
36. Buchan SA, Seo CY, Johnson C, et al. Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval. medRxiv. 2021:12.02.21267156.
37. Wong A. The ethics of HEK 293. Natl Cathol Bioeth Q. 2006;6:473-495. doi: 10.5840/ncbq20066331
38. North Dakota Health. COVID-19 vaccines & fetal cell lines. Updated December 1, 2021. Accessed September 21, 2022. www.health.nd.gov/sites/www/files/documents/COVID%20Vaccine%20Page/COVID-19_Vaccine_Fetal_Cell_Handout.pdf
39. Abbasi J. Widespread misinformation about infertility continues to create COVID-19 vaccine hesitancy. JAMA. 2022;327:1013-1015. doi: 10.1001/jama.2022.2404
40. Halasa NB, Olson SM, Staat MA, et al; ; . Effectiveness of maternal vaccination with mRNA COVID-19 vaccine during pregnancy against COVID-19-associated hospitalization in infants aged < 6 months—17 States, July 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:264-270. doi: 10.15585/mmwr.mm7107e3
41. American College of Obstetricians and Gynecologists. ACOG and SMFM recommend COVID-19 vaccination for pregnant individuals. July 30, 2021. Accessed September 21, 2022. www.acog.org/news/news-releases/2021/07/acog-smfm-recommend-covid-19-vaccination-for-pregnant-individuals#:~:text=%E2%80%9CACOG%20is%20recommending%20vaccination%20of,complications%2C%20and%20because%20it%20isvaccines
42. Brown CM, Vostok J, Johnson H, et al. Outbreak of SARS-CoV-2 infections, including COVID-19 vaccine breakthrough infections, associated with large public gatherings—Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1059-1062. doi: 10.15585/mmwr.mm7031e2
43. Ferdinands JM, Rao S, Dixon BE, et al. Waning 2-dose and 3-dose effectiveness of mRNA against COVID-19-associated emergency department and urgent care encounters and hospitalizations among adults during periods of Delta and Omicron variant predominance—VISION Network, 10 states, August 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:255-263. doi: 10.15585/mmwr.mm7107e2
44. Abu-Raddad LJ, Chemaitelly H, Ayoub HH, et al. Effect of mRNA vaccine boosters against SARS-CoV-2 Omicron infection in Qatar. N Engl J Med. 2022;386:1804-1816. doi: 10.1056/NEJMoa2200797
45. Arbel R, Hammerman A, Sergienko R, et al. BNT162b2 vaccine booster and mortality due to Covid-19. N Engl J Med. 2021;385:2413-2420. doi: 10.1056/NEJMoa2115624
46. Bar-On YM, Goldberg Y, Mandel M, et al. Protection against Covid-19 by BNT162b2 booster across age groups. N Engl J Med. 2021;385:2421-2430. doi: 10.1056/NEJMoa2115926
47. Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 vaccine booster against Covid-19 in Israel. N Engl J Med. 2021;385:1393-1400. doi: 10.1056/NEJMoa2114255
48. Mbaeyi S, Oliver SE, Collins JP, et al. The Advisory Committee on Immunization Practices’ interim recommendations for additional primary and booster doses of COVID-19 vaccines—United States, 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1545-1552. doi: 10.15585/mmwr.mm7044e2
49. Chen X, Chen Z, Azman AS, et al. Neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants induced by natural infection or vaccination: a systematic review and pooled analysis. Clin Infect Dis. 2022;74:734-742. doi: 10.1093/cid/ciab646
50. Atmar RL, Lyke KE, Deming ME, et al; . Homologous and heterologous Covid-19 booster vaccinations. N Engl J Med. 2022;386:1046-1057. doi: 10.1056/NEJMoa2116414
51. Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Updated September 2, 2022. Accessed September 21, 2022. www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html
52. Ackerman CM, Nguyen JL, Ambati S, et al. Clinical and pregnancy outcomes of coronavirus disease 2019 among hospitalized pregnant women in the United States. Open Forum Infect Dis. 2022;9:ofab429. doi: 10.1093/ofid/ofab429
53. Osterman MJK, Valenzuela CP, Martin JA. Maternal and infant characteristics among women with confirmed or presumed cases of coronavirus disease (COVID-19) during pregnancy. National Center for Health Statistics. National Vital Statistics System. Updated August 11, 2022. Accessed September 21, 2022. www.cdc.gov/nchs/covid19/technical-linkage.htm
54. De Rose DU, Salvatori G, Dotta A, et al. SARS-CoV-2 vaccines during pregnancy and breastfeeding: a systematic review of maternal and neonatal outcomes. Viruses. 2022;14:539. doi: 10.3390/v14030539
55. Martins I, Louwen F, Ayres-de-Campos D, et al. EBCOG position statement on COVID-19 vaccination for pregnant and breastfeeding women. Eur J Obstet Gynecol Reprod Biol. 2021;262:256-258. doi: 10.1016/j.ejogrb.2021.05.021
56. Chou J, Thomas PG, Randolph AG. Immunology of SARS-CoV-2 infection in children. Nat Immunol. 2022;23:177-185. doi: 10.1038/s41590-021-01123-9
57. Parcha V, Booker KS, Kalra R, et al. A retrospective cohort study of 12,306 pediatric COVID-19 patients in the United States. Sci Rep. 2021;11:10231. doi: 10.1038/s41598-021-89553-1
58. Marks KJ, Whitaker M, Anglin O, et al; . Hospitalizations of children and adolescents with laboratory-confirmed COVID-19—COVID-NET, 14 states, July 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:271-278. doi: 10.15585/mmwr.mm7107e4
59. Price AM, Olson SM, Newhams MM, et al; . BNT162b2 protection against the Omicron variant in children and adolescents. N Engl J Med. 2022;386:1899-1909. doi: 10.1056/NEJMoa2202826
60. Maldonado YA, O’Leary ST, Banerjee R, et al; Committee on Infectious Diseases, American Academy of Pediatrics. COVID-19 vaccines in children and adolescents. Pediatrics. 2021;148:e2021052336. doi: 10.1542/peds.2021-052336
61. Lontok K. How effective are COVID-19 vaccines in immunocompromised people? American Society for Microbiology. August 12, 2021. Accessed September 21, 2022. https://asm.org/Articles/2021/August/How-Effective-Are-COVID-19-Vaccines-in-Immunocompr
62. Meiring S, Tempia S, Bhiman JN, et al; . Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at high viral loads among hospitalized immunocompromised persons living with human immunodeficiency virus, South Africa. Clin Infect Dis. 2022;75:e144-e156. doi: 10.1093/cid/ciac077
63. Bar-On YM, Goldberg Y, Mandel M, et al. Protection by 4th dose of BNT162b2 against Omicron in Israel. medRxiv. 2022: 02.01.22270232. doi: 10.1101/2022.02.01.22270232
64. Monto AS, DeJonge PM, Callear AP, et al. Coronavirus occurrence and transmission over 8 years in the HIVE cohort of households in Michigan. J Infect Dis. 2020;222:9-16. doi: 10.1093/infdis/jiaa161
65. Petrie JG, Bazzi LA, McDermott AB, et al. Coronavirus occurrence in the Household Influenza Vaccine Evaluation (HIVE) cohort of Michigan households: reinfection frequency and serologic responses to seasonal and severe acute respiratory syndrome coronaviruses. J Infect Dis. 2021;224:49-59. doi: 10.1093/infdis/jiab161
66. Kirby AE, Walters MS, Jennings WC, et al. Using wastewater surveillance data to support the COVID-19 response—United States, 2020–2021. MMWR Morb Mortal Wkly Rep. 2021;70:1242-1244. doi: 10.15585/mmwr.mm7036a2
Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.1 Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.2-4
In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”
SIDEBAR
COVID-19 vaccination resources
Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States
Centers for Disease Control and Prevention
www.cdc.gov/vaccines/covid-19/clinical-considerations/interimconsiderations-us.html
COVID-19 ACIP vaccine recommendations
Advisory Committee on Immunization Practices (ACIP)
www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html
MMWR COVID-19 reports
Morbidity and Mortality Weekly Report
www.cdc.gov/mmwr/Novel_Coronavirus_Reports.html
A literature hub for tracking up-to-date scientific information about the 2019 novel coronavirus
National Center for Biotechnology Information of the National Library of Medicine
www.ncbi.nlm.nih.gov/research/coronavirus
Understanding COVID-19 vaccines
National Institutes of Health COVID-19 Research
https://covid19.nih.gov/treatments-and-vaccines/covid-19-vaccines
How COVID-19 affects pregnancy
National Institutes of Health COVID-19 Research
SARS-CoV-2 virology
As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.7
After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.5 The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.
Basic mRNA vaccine immunology
Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.8
mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.
mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:
- They are nonreplicating.
- They do not integrate into the host genome.
- They are highly effective.
- They can produce antibody and cellular immunity.
- They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.
Continue to: Vaccines against SARS-CoV-2
Vaccines against SARS-CoV-2
Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).9
Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)
The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.
The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.
Efficacy of COVID-19 vaccines
The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.10 This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-confirmed COVID-19 at 3-month follow-up.10 Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.
Continue to: Data from trials...
Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.17
Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.18 During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.19
In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.16 A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.20 The efficacy of the vaccines is summarized in TABLE 1.21-24
Even in patients who have natural infection, several studies have shown that COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.
Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.29
Continue to: Vaccine adverse effects
Vaccine adverse effects: Common, rare, myths
Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 121-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.a
Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.30,31
Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.
A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.33 Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.34 In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.34
A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.35 Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.
Continue to: There is emerging evidence...
There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.36 That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.
TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.36 The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.36) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations36 (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).
Myths surrounding vaccination
Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).37 There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.38
Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.39 No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.40,41
Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.8
Continue to: Boosters and vaccine mix-and-match
Boosters and vaccine mix-and-match
As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.42 There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.42 Five patients were hospitalized; none died.42 A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.
Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.43 Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.
Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.49
Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity50 (TABLE 251).
Vaccination in special populations
Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”
Continue to: Pregnant patients
Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.52 CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.53
A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from COVID-19 vaccination.54 Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.
Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.55
Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.56 In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.57
Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:
- the absence of comorbidities often seen in adults
- evidence that pediatric patients might have reduced expression of ACE-2
- a more active T-cell response in infected children, due to an active thymus.56
Continue to: Although the number of children affected...
Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.58 The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.58 Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.59,60
Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.61 Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.62 Antibody response to vaccination was also less robust in this group.
There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.63 Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.b
Predictions (or, why is a COVID-19 vaccine important?)
What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.64 First, only relative immunity is produced after infection with a seasonal coronavirus.64 Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.65 Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.
The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.66 During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.
Continue to: At approximately that time...
At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.57 In view of warning signs from wastewater surveillance, priorities for vaccination should be to:
- increase uptake in the hesitant
- get boosters to the eligible
- prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.
As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.
awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html
b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.
CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]
Worldwide and across many diseases, vaccines have been transformative in reducing mortality—an effect that has been sustained with vaccines that protect against COVID-19.1 Since the first cases of SARS-CoV-2 infection were reported in late 2019, the pace of scientific investigation into the virus and the disease—made possible by unprecedented funding, infrastructure, and public and private partnerships—has been explosive. The result? A vast body of clinical and laboratory evidence about the safety and effectiveness of SARS-CoV-2 vaccines, which quickly became widely available.2-4
In this article, we review the basic underlying virology of SARS-CoV-2; the biotechnological basis of vaccines against COVID-19 that are available in the United States; and recommendations on how to provide those vaccines to your patients. Additional guidance for your practice appears in a select online bibliography, “COVID-19 vaccination resources.”
SIDEBAR
COVID-19 vaccination resources
Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States
Centers for Disease Control and Prevention
www.cdc.gov/vaccines/covid-19/clinical-considerations/interimconsiderations-us.html
COVID-19 ACIP vaccine recommendations
Advisory Committee on Immunization Practices (ACIP)
www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html
MMWR COVID-19 reports
Morbidity and Mortality Weekly Report
www.cdc.gov/mmwr/Novel_Coronavirus_Reports.html
A literature hub for tracking up-to-date scientific information about the 2019 novel coronavirus
National Center for Biotechnology Information of the National Library of Medicine
www.ncbi.nlm.nih.gov/research/coronavirus
Understanding COVID-19 vaccines
National Institutes of Health COVID-19 Research
https://covid19.nih.gov/treatments-and-vaccines/covid-19-vaccines
How COVID-19 affects pregnancy
National Institutes of Health COVID-19 Research
SARS-CoV-2 virology
As the SARS-CoV-2 virus approaches the host cell, normal cell proteases on the surface membrane cause a change in the shape of the SARS-CoV-2 spike protein. That spike protein conformation change allows the virus to avoid detection by the host’s immune system because its receptor-binding site is effectively hidden until just before entry into the cell.5,6 This process is analogous to a so-called lock-and-key method of entry, in which the key (ie, spike protein conformation) is hidden by the virus until the moment it is needed, thereby minimizing exposure of viral contents to the cell. As the virus spreads through the population, it adapts to improve infectivity and transmissibility and to evade developing immunity.7
After the spike protein changes shape, it attaches to an angiotensin-converting enzyme 2 (ACE-2) receptor on the host cell, allowing the virus to enter that cell. ACE-2 receptors are located in numerous human tissues: nasopharynx, lung, gastrointestinal tract, heart, thymus, lymph nodes, bone marrow, brain, arterial and venous endothelial cells, and testes.5 The variety of tissues that contain ACE-2 receptors explains the many sites of infection and location of symptoms with which SARS-CoV-2 infection can manifest, in addition to the respiratory system.
Basic mRNA vaccine immunology
Although messenger RNA (mRNA) vaccines seem novel, they have been in development for more than 30 years.8
mRNA encodes the protein for the antigen of interest and is delivered to the host muscle tissue. There, mRNA is translated into the antigen, which stimulates an immune response. Host enzymes then rapidly degrade the mRNA in the vaccine, and it is quickly eliminated from the host.
mRNA vaccines are attractive vaccine candidates, particularly in their application to emerging infectious diseases, for several reasons:
- They are nonreplicating.
- They do not integrate into the host genome.
- They are highly effective.
- They can produce antibody and cellular immunity.
- They can be produced (and modified) quickly on a large scale without having to grow the virus in eggs.
Continue to: Vaccines against SARS-CoV-2
Vaccines against SARS-CoV-2
Two vaccines (from Pfizer-BioNTech [Comirnaty] and from Moderna [Spikevax]) are US Food and Drug Administration (FDA)–approved for COVID-19; both utilize mRNA technology. Two other vaccines, which do not use mRNA technology, have an FDA emergency use authorization (from Janssen Biotech, of Johnson & Johnson [Janssen COVID-19 Vaccine] and from Novavax [Novavax COVID-19 Vaccine, Adjuvanted]).9
Pfizer-BioNTech and Moderna vaccines. The mRNA of these vaccines encodes the entire spike protein in its pre-fusion conformation, which is the antigen that is replicated in the host, inducing an immune response.10-12 (Recall the earlier lock-and-key analogy: This conformation structure ingeniously replicates the exposed 3-dimensional key to the host’s immune system.)
The Janssen vaccine utilizes a viral vector (a nonreplicating adenovirus that functions as carrier) to deliver its message to the host for antigen production (again, the spike protein) and an immune response.
The Novavax vaccine uses a recombinant nanoparticle protein composed of the full-length spike protein.13,14 In this review, we focus on the 2 available mRNA vaccines, (1) given their FDA-authorized status and (2) because Centers for Disease Control and Prevention (CDC) recommendations indicate a preference for mRNA vaccination over viral-vectored vaccination. However, we also address key points about the Janssen (Johnson & Johnson) vaccine.
Efficacy of COVID-19 vaccines
The first study to document the safety and efficacy of a SARS-CoV-2 vaccine (the Pfizer-BioNTech vaccine) was published just 12 months after the onset of the pandemic.10 This initial trial demonstrated a 95% efficacy in preventing symptomatic, laboratory-confirmed COVID-19 at 3-month follow-up.10 Clinical trial data on the efficacy of COVID-19 vaccines have continued to be published since that first landmark trial.
Continue to: Data from trials...
Data from trials in Israel that became available early in 2021 showed that, in mRNA-vaccinated adults, mechanical ventilation rates declined strikingly, particularly in patients > 70 years of age.15,16 This finding was corroborated by data from a surveillance study of multiple US hospitals, which showed that mRNA vaccines were > 90% effective in preventing hospitalization in adults > 65 years of age.17
Data published in May 2021 showed that the Pfizer-BioNTech and Moderna vaccines were 94% effective in preventing COVID-19-related hospitalization.18 During the end of the Delta wave of the pandemic and the emergence of the Omicron variant of SARS-CoV-2, unvaccinated people were 5 times as likely to be infected as vaccinated people.19
In March 2022, data from 21 US medical centers in 18 states demonstrated that adults who had received 3 doses of the vaccine were 94% less likely to be intubated or die than those who were unvaccinated.16 A July 2022 retrospective cohort study of 231,037 subjects showed that the risk of hospitalization for acute myocardial infarction or for stroke after COVID-19 infection was reduced by more than half in fully vaccinated (ie, 2 doses of an mRNA vaccine or the viral vector [Janssen/Johnson & Johnson] vaccine) subjects, compared to unvaccinated subjects.20 The efficacy of the vaccines is summarized in TABLE 1.21-24
Even in patients who have natural infection, several studies have shown that COVID-19 vaccination after natural infection increases the level and durability of immune response to infection and reinfection and improves clinical outcomes.9,20,25,26 In summary, published literature shows that (1) mRNA vaccines are highly effective at preventing infection and (2) they augment immunity achieved by infection with circulating virus.
Breakthrough infection. COVID-19 mRNA vaccines are associated with breakthrough infection (ie, infections in fully vaccinated people), a phenomenon influenced by the predominant viral variant circulating, the level of vaccine uptake in the studied population, and the timing of vaccination.27,28 Nevertheless, vaccinated people who experience breakthrough infection are much less likely to be hospitalized and die compared to those who are unvaccinated, and vaccination with an mRNA vaccine is more effective than immunity acquired from natural infection.29
Continue to: Vaccine adverse effects
Vaccine adverse effects: Common, rare, myths
Both early mRNA vaccine trials reported common minor adverse effects after vaccination (TABLE 121-24). These included redness and soreness at the injection site, fatigue, myalgias, fever, and nausea, and tended to be more common after the second dose. These adverse effects are similar to common adverse effects seen with other vaccines. Counseling information about adverse effects can be found on the CDC website.a
Two uncommon but serious adverse effects of COVID-19 vaccination are myocarditis or pericarditis after mRNA vaccination and thrombosis with thrombocytopenia syndrome (TTS), which occurs only with the Janssen vaccine.30,31
Myocarditis and pericarditis, particularly in young males (12 to 18 years), and mostly after a second dose of vaccine, was reported in May 2021. Since then, several studies have shown that the risk of myocarditis is slightly higher in males < 40 years of age, with a predicted case rate ranging from 1 to 10 excess cases for every 1 million patients vaccinated.30,32 This risk must be balanced against the rate of myocarditis associated with SARS-CoV-2 infection.
A large study in the United States demonstrated that the risk of myocarditis for those who contract COVID-19 is 16 times higher than it is for those who are disease free.33 Observational safety data from April 2022 showed that men ages 18 to 29 years had 7 to 8 times the risk of heart complications after natural infection, compared to men of those ages who had been vaccinated.34 In this study of 40 US health care systems, the incidence of myocarditis or pericarditis in that age group ranged from 55 to 100 cases for every 100,000 people after infection and from 6 to 15 cases for every 100,000 people after a second dose of an mRNA vaccine.34
A risk–benefit analysis conducted by the Advisory Committee on Immunization Practices (ACIP) ultimately supported the conclusions that (1) the risk of myocarditis secondary to vaccination is small and (2) clear benefits of preventing infection, hospitalization, death, and continued transmission outweigh that risk.35 Study of this question, utilizing vaccine safety and reporting systems around the world, has continued.
Continue to: There is emerging evidence...
There is emerging evidence that extending the interval between the 2 doses of vaccine decreases the risk of myocarditis, particularly in male adolescents.36 That evidence ultimately led the CDC to recommend that it might be optimal that an extended interval (ie, waiting 8 weeks between the first and second dose of vaccine), in particular for males ages 12 to 39 years, could be beneficial in decreasing the risk of myocarditis.
TTS. A population risk–benefit analysis of TTS was conducted by ACIP while use of the Janssen vaccine was paused in the United States in December 2021.36 The analysis determined that, although the risk of TTS was largely in younger women (18 to 49 years; 7 cases for every 1 million vaccine doses administered), benefits of the vaccine in preventing death, hospitalization, and a stay in the intensive care unit (ICU)—particularly if vaccination was delayed or there was a high rate of community infection—clearly outweighed risks. (The CDC estimated an incidence of 2 cases of TTS with more than 3 million doses of Janssen vaccine administered; assuming moderate transmission kinetics, more than 3500 hospitalizations and more than 350 deaths were prevented by vaccination.36) Ultimately, after the CDC analysis was released, vaccination utilizing the Janssen product resumed; however, the CDC offered the caveat that the Janssen vaccine should be used only in specific situations36 (eg, when there has been a severe reaction to mRNA vaccine or when access to mRNA or recombinant nanoparticle vaccine is limited).
Myths surrounding vaccination
Myth #1: SARS-CoV-2 vaccines contain tissue from aborted fetuses. This myth, which emerged during development of the vaccines, is often a conflation of the use of embryonic cell lines obtained decades ago to produce vaccines (a common practice—not only for vaccines but common pharmaceuticals and foods).37 There are no fetal cells or tissue in any SARS-CoV-2 vaccines, and the vaccines have been endorsed by several faith organizations.38
Myth #2: SARS-CoV-2 vaccines can cause sterility in men and women. This myth originated from a report in early December 2020 seeking to link a similarity in a protein involved in placental–uterine binding and a portion of the receptor-binding domain antigen produced by the vaccine.39 No studies support this myth; COVID-19 vaccines are recommended in pregnancy by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine.40,41
Myth #3: mRNA SARS-CoV-2 vaccines alter a recipient’s DNA. mRNA vaccines are broken down by cellular enzymes. They cannot be integrated into the host genome.8
Continue to: Boosters and vaccine mix-and-match
Boosters and vaccine mix-and-match
As the COVID-19 pandemic persists, with new variants of concern emerging, it has also become clear that immunity wanes. In July 2021, the first report was published after a cluster of breakthrough infections occurred in a town in Massachusetts.42 There was no recommendation, at the time, for a booster; the Delta variant was the predominant circulating strain. In this outbreak, there were 469 cases, 74% of which were in people who had received 2 doses of an mRNA vaccine.42 Five patients were hospitalized; none died.42 A key takeaway from this outbreak was that vaccination prevented death, even in the face of fairly wide breakthrough infection.
Newer data show that, although vaccine effectiveness against hospitalization was greater than 90% for the first 2 months after a third dose, it waned to 78% by 4 months.43 Published data, combined with real-world experience, show that boosters provide additional reduction in the risk of death and hospitalization. This has led to a recommendation that all patients ≥ 5 years of age receive a booster.19,26,43-48 The CDC now recommends that people who are ages 12 years and older receive a bivalent booster (containing both wild-type and Omicron-variant antigens) ≥ 2 months after their most recent booster or completed series.
Future booster recommendations will consider the durability of the immune response over time (measured against the original immunizing virus) and the mutation rate of the virus.49
Given the limited supply of vaccine early in the pandemic, and the potential for future limitations, there was early interest in studying so-called mix-and-match SARS-CoV-2 vaccination—that is, receiving one product as a first series and then a different product as a booster, also known as heterologous booster vaccination. Although it is preferred that the 2 doses of the primary series be of the same vaccine product, studies that have examined this question support heterologous boosting as an acceptable approach to protective immunity50 (TABLE 251).
Vaccination in special populations
Three groups of patients have unique host characteristics that are important to consider when providing COVID-19 vaccination in your practice: pregnant patients, children, and patients in the broad category of “immunocompromised status.”
Continue to: Pregnant patients
Pregnant patients with SARS-CoV-2 infection are more likely to be hospitalized and have a higher risk of a stay in the ICU and need for mechanical ventilation. In a study of the course of illness in symptomatic pregnant patients who were hospitalized, 16.2% were admitted to an ICU and 8.5% were mechanically ventilated.52 CDC observational data have consistently supported the finding that (1) pregnant patients infected with SARS-CoV-2 are at increased risk of preterm labor and (2) their newborns are at increased risk of low birth weight and requiring admission to the neonatal ICU.53
A systematic review of 46 studies in pregnant and lactating patients showed no increased risk of adverse effects from COVID-19 vaccination.54 Furthermore, data from multiple studies demonstrate that immunoglobulin G antibodies cross the placenta to protect the infant at birth (ie, are found in umbilical cord blood and neonatal blood) and are found in breast milk. The precise kinetics and durability of these antibodies are unknown.
Pregnant patients were initially excluded from vaccine trials (although there were some patients ultimately found to be pregnant, or who became pregnant, during the trial). Careful examination of vaccine safety and efficacy data has supported the American College of Obstetricians and Gynecologists and European Board and College of Obstetrics and Gynaecology (EBCOG) recommendation that all pregnant patients be vaccinated. Furthermore, EBCOG recommends vaccination during the period of breastfeeding.55
Children. A major challenge during the pandemic has been to understand (1) the effect that infection with SARS-CoV-2 has on children and (2) the role of children in transmission of the virus. Although most children with COVID-19 have mild symptoms, a few require hospitalization and mechanical ventilation and some develop life-threatening multisystem inflammatory syndrome.56 In a large, retrospective study of more than 12,000 children with COVID-19, 5.3% required hospitalization and almost 20% of that subset were admitted to the ICU.57
Various hypotheses have been put forward to describe and explain the differences in disease expression between children and adults. These include:
- the absence of comorbidities often seen in adults
- evidence that pediatric patients might have reduced expression of ACE-2
- a more active T-cell response in infected children, due to an active thymus.56
Continue to: Although the number of children affected...
Although the number of children affected by severe SARS-CoV-2 infection is less than the number of adults, there have been important trends observed in infection and hospitalization as different variants have arisen.58 The Delta and Omicron variants have both been associated with a disturbing trend in the rate of hospitalization of pediatric patients, particularly from birth to 4 years—patients who were ineligible for vaccination at the time of the study.58 Ultimately, these data, combined with multiple studies of vaccine effectiveness in this age group, have led to an emergency use authorization for the Pfizer-BioNTech vaccination in pediatric populations and a recommendation from the American Academy of Pediatrics that all children ages 6 months and older be vaccinated.59,60
Immunocompromised patients. Patients broadly classified as immunocompromised have raised unique concerns. These patients have conditions such as malignancy, primary or secondary immunodeficiency, diabetes, and autoimmune disease; are taking certain classes of medication; or are of older age.61 Early in the pandemic, data showed that immunocompromised hosts could shed virus longer than hosts with an intact immune system—adding to their risk of transmitting SARS-CoV-2 and of viral adaptation for immune escape.62 Antibody response to vaccination was also less robust in this group.
There are limited data that demonstrate a short-lived reduction in risk of infection (in that study, Omicron was the prominent variant) with a fourth dose of an mRNA vaccine.63 Based on these data and FDA approval, the CDC recommends (1) an additional third primary dose and (2) a second booster for people who are moderately or severely immunocompromised. For those ages 50 years or older, a second booster is now required for their vaccination to be considered up to date.b
Predictions (or, why is a COVID-19 vaccine important?)
What does the future hold for our struggle with COVID-19? Perhaps we can learn lessons from the study of the 4 known seasonal coronaviruses, which cause the common cold and circulate annually.64 First, only relative immunity is produced after infection with a seasonal coronavirus.64 Studies of antibodies to seasonal coronaviruses seem to suggest that, although antibody titers remain high, correlation with decreased infection is lacking.65 Second, a dominant strain or 2 emerges each season, probably as a result of genetic variation and selective pressure for immune escape from neutralizing antibodies or cellular immunity.
The complex relationship among competing immune response duration, emergence of viral immune escape, increasing viral transmissibility, and societal viral source control (through vaccination, masking, distancing, testing, isolation, and treatment) widens the confidence bounds on our estimates of what the future holds. Late in 2020, the CDC began reporting wastewater surveillance data as a method for monitoring, and predicting changes in, community spread.66 During Spring 2022, the CDC reported an increase in detection of SARS-CoV-2 from a third of wastewater sampling sites around the United States. This observation coincided with (1) appearance of still more transmissible BA.2 and, later, BA.2.12.1 variants and (2) general relaxing of masking and social distancing guidelines, following the decline of the Omicron variant.
Continue to: At approximately that time...
At approximately that time, application to the FDA for a fourth shot (or a second booster) by Pfizer-BioNTech had been approved for adults > 50 years of age, at > 4 months after their previous vaccination.57 In view of warning signs from wastewater surveillance, priorities for vaccination should be to:
- increase uptake in the hesitant
- get boosters to the eligible
- prepare to tackle either seasonal or sporadic recurrence of COVID-19—whichever scenario the future brings.
As an example of how these priorities have been put into action, in September 2022, the FDA approved, and the CDC recommended, new bivalent boosters for everyone ≥ 12 years of age (Pfizer-BioNTech) or for all those ≥ 18 years of age (Moderna), to be administered ≥ 2 months after receipt of their most recent booster or primary series.
awww.cdc.gov/coronavirus/2019-ncov/vaccines/index.html
b Visit www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html for more guidance on COVID-19 vaccination for immunocompromised patients.
CORRESPONDENCE
John L. Kiley, MD, 3551 Roger Brooke Drive, Fort Sam Houston, TX 78234; [email protected]
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19. Johnson AG, Amin AB, Ali AR, et al. COVID-19 incidence and death rates among unvaccinated and fully vaccinated adults with and without booster doses during periods of Delta and Omicron variant emergence—25 U.S. jurisdictions, April 4–December 25, 2021. MMWR Morb Mortal Wkly Rep. 2022;71:132-138. doi: 10.15585/mmwr.mm7104e2
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25. Greaney AJ, Loes AN, Gentles LE, et al. Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection. Sci Transl Med. 2021;13:eabi9915. doi: 10.1126/scitranslmed.abi9915
26. Hall V, Foulkes S, Insalata F, et al. Protection against SARS-CoV-2 after Covid-19 vaccination and previous infection. N Engl J Med. 2022;386:1207-1220. doi: 10.1056/NEJMoa2118691
27. Klompas M. Understanding breakthrough infections following mRNA SARS-CoV-2 avccination. JAMA. 2021;326:2018-2020. doi: 10.1001/jama.2021.19063
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29. Yu Y, Esposito D, Kang Z, et al. mRNA vaccine-induced antibodies more effective than natural immunity in neutralizing SARS-CoV-2 and its high affinity variants. Sci Rep. 2022;12:2628. doi: 10.1038/s41598-022-06629-2
30. Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices—United States, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70:977-982. doi: 10.15585/mmwr.mm7027e2
31. MacNeil JR, Su JR, Broder KR, et al. Updated recommendations from the Advisory Committee on Immunization Practices for use of the Janssen (Johnson & Johnson) COVID-19 vaccine after reports of thrombosis with thrombocytopenia syndrome among vaccine recipients—United States, April 2021. MMWR Morb Mortal Wkly Rep. 2021;70:651-656. doi: 10.15585/mmwr.mm7017e4
32. Patone M, Mei XW, Handunnetthi L, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med. 2022;28:410-422. doi: 10.1038/s41591-021-01630-0
33. Boehmer TK, Kompaniyets L, Lavery AM, et al. Association between COVID-19 and myocarditis using hospital-based administrative data—United States, March 2020–January 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1228-1232. doi: 10.15585/mmwr.mm7035e5
34. Block JP, Boehmer TK, Forrest CB, et al. Cardiac complications after SARS-CoV-2 infection and mRNA COVID-19 vaccination—PCORnet, United States, January 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:517-523. doi: 10.15585/mmwr.mm7114e1
35. Rosemblum H. COVID-19 vaccines in adults: benefit–risk discussion. Centers for Disease Control and Prevention. July 22, 2021. Accessed September 21, 2022. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/05-COVID-Rosenblum-508.pdf
36. Buchan SA, Seo CY, Johnson C, et al. Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, Canada: by vaccine product, schedule and interval. medRxiv. 2021:12.02.21267156.
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39. Abbasi J. Widespread misinformation about infertility continues to create COVID-19 vaccine hesitancy. JAMA. 2022;327:1013-1015. doi: 10.1001/jama.2022.2404
40. Halasa NB, Olson SM, Staat MA, et al; ; . Effectiveness of maternal vaccination with mRNA COVID-19 vaccine during pregnancy against COVID-19-associated hospitalization in infants aged < 6 months—17 States, July 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:264-270. doi: 10.15585/mmwr.mm7107e3
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43. Ferdinands JM, Rao S, Dixon BE, et al. Waning 2-dose and 3-dose effectiveness of mRNA against COVID-19-associated emergency department and urgent care encounters and hospitalizations among adults during periods of Delta and Omicron variant predominance—VISION Network, 10 states, August 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71:255-263. doi: 10.15585/mmwr.mm7107e2
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59. Price AM, Olson SM, Newhams MM, et al; . BNT162b2 protection against the Omicron variant in children and adolescents. N Engl J Med. 2022;386:1899-1909. doi: 10.1056/NEJMoa2202826
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61. Lontok K. How effective are COVID-19 vaccines in immunocompromised people? American Society for Microbiology. August 12, 2021. Accessed September 21, 2022. https://asm.org/Articles/2021/August/How-Effective-Are-COVID-19-Vaccines-in-Immunocompr
62. Meiring S, Tempia S, Bhiman JN, et al; . Prolonged shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at high viral loads among hospitalized immunocompromised persons living with human immunodeficiency virus, South Africa. Clin Infect Dis. 2022;75:e144-e156. doi: 10.1093/cid/ciac077
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PRACTICE RECOMMENDATIONS
› Vaccinate all adults (≥ 18 years) against COVID-19, based on recommendations for the initial series and boosters. A
› Vaccinate patients against COVID-19 with evidence-based assurance that doing so reduces disease-related risk of hospitalization, myocardial infarction, stroke, need for mechanical ventilation, and death. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
