COVID-19, Vaccines, Prevention

by David O. Freedman, M.D. last updated 2022-04-28 13:39:35.339836-04:00 © Antimicrobial Therapy, Inc.
COVID-19 Post-exposure Prophylaxis, Primary Prevention, Vaccines

Primary Prevention, Prophylaxis

  • Primary prevention / pre-exposure prophylaxis for at risk individuals
    • Evusheld (tixagevimab + cilgavimab), administered as two separate consecutive intramuscular injections (one injection per monoclonal antibody, given in immediate succession; Tixagevimab 300 mg/1.5 mL IM (single dose) + Cilgavimab 300 mg/1.5 mL IM (single dose)), may only be used as PRE-exposure prophylaxis for adults and pediatric individuals (12 years of age and older weighing at least 40 kg) who are not currently infected with SARS-CoV-2 and who have not recently been exposed to an individual infected with SARS-CoV-2, and who have:
      • Moderate to severely compromised immune systems due to a medical condition or due to taking immunosuppressive medications or treatments and may not mount an adequate immune response to COVID-19 vaccination (examples of such medical conditions or treatment s can be found in the fact sheet for health care providers) or
      • A history of severe adverse reactions to a COVID-19 vaccine and/or component(s) of those vaccines, therefore vaccination with an available COVID-19 vaccine, according to the approved or authorized schedule, is not recommended.
    • Evusheld is approved through an EUA for pre-exposure prophylaxis, but is NOT approved for post-exposure prophylaxis nor for treatment of active, current SARS-CoV-2 infection
    • In the pivotal, RC clinical trial, Evusheld recipients had a  77% reduced risk of developing COVID-19 compared to those who received a placebo.  The estimated durability of Evusheld is up to 6 months protection.
  • Primary prevention / post-exposure prophylaxis for previously uninfected household contacts:
    • REGEN-COV, administered 1200 mg as REGEN-COV (600 mg Casirivimab + 600 mg Imdevimab ) subcutaneously one time, OR  Bamlanivimab (700 mg) and etesevimab (1400 mg), administered intravenously together, may only be used as post-exposure prophylaxis for adults and pediatric individuals (12 years of age and older weighing at least 40 kg) who are:
      • At high risk for progression to severe COVID-19, including hospitalization or death and
      • Not fully vaccinated or who are not expected to mount an adequate immune response to complete SARS-CoV-2 vaccination (for example, people with immunocompromising conditions, including those taking immunosuppressive medications) and
        • Have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria per Centers for Disease Control and Prevention (CDC), or
        • Who are at high risk of exposure to an individual infected with SARS-CoV-2 because of occurrence of SARS-CoV-2 infection in other individuals in the same institutional setting (for example, nursing homes or prisons)
    • Relative risk reduction 81.4% relative risk reduction in COVID-19 infection (N Engl J Med, Aug 4, 2021)

Vaccine Preferences (US)

  • Vaccine information is divided into summary tables for US and WHO authorized vaccines and individual vaccine pages. See below. For complete information covering efficacy, adverse effects, and mix and match dosing considerations for primary and booster doses: see Pfizer, Moderna, Janssen/J&J, NovavaxAstraZeneca, SinoPharm, Sinovac, Sputnik, Bharat.
  • Vaccine Efficacy (VE) Against the Omicron Variants
    • VE based on breakthrough infections and hospitalizations in the Omicron era is increasingly difficult to calculate due to the variability in vaccine types, numbers of doses, and spacing of doses in the general population, and due to the decentralized data collection mechanisms especially for cases confirmed by self-tests in countries with federal structures (including the US).
    • Available observational and laboratory-based data (neutralizing titers) continue to support the need for triple vaccination in those with no history of prior infection.
    • For Omicron, 3-dose VE is more than 95% against hospitalization, more than 95% against death, and approximately 50% against symptomatic infection. In marked contrast, 2-dose VE is approximately 50% against hospitalization, 60% against death, and no more than 25% against symptomatic infection. 
    • Some concern exists that the low dose of Pfizer vaccine used for children aged 5-11 years is already less effective at preventing infection and hospitalization against Omicron in that age group in whom no booster is currently recommended. 
    • The duration of vaccine efficacy in triple vaccinated persons remains unclear, but T-cell immunity which protects against severe disease appears to last at least 6 months.
    • Recipients of 2 doses of mRNA vaccine appear to have zero or minimal neutralizing antibody titers against Omicron
      • booster doses of non-mRNA vaccines are unproven in preventing population transmission with Omicron and transmission rates appear independent of vaccination status.
  • Bottom-line vaccination messaging for the three vaccines currently approved in the US :
    • Only mRNA vaccines (Pfizer, Moderna) should be used
      • Janssen/J&J is second-line and for uncommon situations due to wide availability of mRNA vaccines and complete absence of life-threatening adverse effects
      • In resource limited environments Janssen/J&J vaccine with ease of storage will still save lives when other vaccines not available.
    • Three doses of mRNA vaccine or a heterolgous adenovirus then mRNA series are the only current effective strategies against the Omicron variant; prior COVID infection likely can substitute for 1 of the 3 vaccines doses.
    • The third vaccine dose in immunocompromised persons is not a booster but rather an additional primary dose to induce initial immunity in those unable to achieve it in the first place.
      • Dose 4  as a booster in the immunocompromised population is  recommended.
  • Against pre-Omicron SARS-COV-2 variants, substantial data indicate that the Moderna vaccine has both a VE and durability advantage over the Pfizer vaccine (likely due to the higher mRNA dose in the primary series), and that a single dose of Janssen/J&J vaccine, which is no longer a preferred vaccine in the US is inadequate. Comparison data after the 3rd dose (6-month booster) of mRNA vaccines are not yet available
    • Two primary doses of an adenovirus vectored vaccine (Astra Zeneca or Janssen) are robust in preventing severe disease in the short run, but given an mRNA vaccine for dose 2 is a significantly superior strategy.
    • Adenovirus vaccines are progressively less favored by guideline making bodies in countries where vaccine supplies are ample.

Authorized Vaccines

U.S. FDA Authorization

  • The following COVID-19 vaccines have U.S. FDA authorization
  • Janssen/J&J vaccine is now considered second line only to be used in extenuating circumstances
  • See individual vaccine pages for complete summaries: Pfizer, Moderna, J&J

Fully Vaccinated versus Up to Date Status

  • CDC Definition of "fully-vaccinated".  Status for purposes of public health, mandates or US entry.  Fully vaccinated means a person has received their primary series of COVID-19 vaccines. US FDA-authorized/approved vaccine: ≥ 2 weeks following receipt of the second dose in a 2-dose series (Moderna [aged ≥ 18 years: 0.5 mL; 100 µg] or Pfizer [aged 5-11 years: 0.2 mL; 10 µg or aged ≥ 12 years: 0.3 mL; 30 µg]) or ≥ 2 weeks following receipt of 1 dose of a single-dose series (Janssen/J&J [aged ≥ 18 years: 0.5 mL; 5x1010 viral particles]).  Moderately or severely immunocompromised persons need an additional primary dose to be fully-vaccinated.

  • CDC Definition of "Up to date".  Up to date means a person has received all recommended COVID-19 vaccines, including a booster dose when eligible (boosters not indicated for all ages).  A person is considered both “boosted” and up to date right after getting their booster dose.   A person is up to date with their COVID-19 vaccination if they have received all recommended doses in the primary series and one booster when eligible. Getting a second booster is not necessary to be considered up to date at this time.  Up to date status alone affects recommendations for quarantine/isolation. 

Vaccine

Pfizer-BioNTech COVID-19 Vaccine (Comirnaty, mRNA BNT162b2)

Moderna COVID-19 Vaccine (Spikevax, mRNA-1273) Janssen COVID-19 Vaccine
(Janssen/Johnson & Johnson,
Ad26.COV2.S). No longer a preferred vaccine in the US.
 

Pfizer and Moderna mRNA vaccines are interchangeable for all doses. See vaccine page for full details

Pfizer and Moderna mRNA vaccines are interchangeable for all doses.See vaccine page for full details Janssen/J&J vaccine should not be used, whether for a primary, first booster, or second booster dose; an mRNA vaccine should be used for all subsequent indicated doses in previous Janssen/J&J vaccinees.  See vaccine page for full details
Age

≥ 12 yrs in US/Canada/EU/WHO EUL. ≥ 18yrs
most other countries. 5-11 year old authorization for pediatric dose (10 μg) in US/Canada/WHO EUL. Three dose series (3 μg) for age <5 yrs; EUA is expected end Q2 2022.

≥ 18 yrs (100 µg in USA/Canada/EU). ≥ 12 yrs in Canada/EU (100 µg per dose)

≥ 18 yrs

Type Lipid nanoparticle (LNP) encapsulated mRNA Lipid nanoparticle (LNP) encapsulated mRNA Non-replicating adenovirus vector
Primary Dosing in persons >12 years (including immunocompromised; including additional primary dose)

0.3 mL IM (30 µg); 2 doses 3-8 weeks apart. 8 weeks preferred for ages 12-64.  3 weeks preferred for >65 yrs, immunocompromised, and persons who need rapid protection.

 

Moderate and severe immunocompromise: third primary dose (0.3 mL; 30 µg) 28 days after dose 2. WHO EUL prefers 1-3 months.

0.5 mL IM (100 µg); 4-8 weeks apart 8 weeks preferred for ages 18-64. 3 weeks preferred for >65 yrs, immunocompromised, and persons who need rapid protection. Not approved in US for ages 12-17.

 

Moderate and severe immunocompromise:  third primary dose (100 µg; dose 3) 28 days after dose 2. However give 50 µg as additional dose 2 months after a primary dose of Janssen/J&J.

0.5 mL IM (5 X 1010 virions) x 1 dose to be used only in healthy adults unable to receive an mRNA vaccine.

 

Moderate and severe immunocompromise: additional dose with an mRNA vaccine at least 28 days after the primary dose if previously given dose 1 with Janssen/J&J vaccine.

Primary Dosing in persons 5-11 years (including immunocompromised; including additional primary dose)

0.2 mL IM (10 µg) pediatric preparation; 2 doses 21 days apart (indefinite delay is acceptable).  No data on longer interval in this age group.

 

Severe immunocompromise:  Additional primary dose (dose 3, 0.2 mL; 10µg): at least 28 days after dose 2.  WHO prefers 1-3 month interval

 Not approved.  Not approved.
Initial Booster Dose (US guidelines presented; wide national variations regarding boosters)

0.3 ml IM  (30 µg) same as primary dose in persons aged >12 years, 5 months after completion of primary series.

 

Moderate and severe immunocompromise this is dose 4 (30 µg) to be given 3 months after dose 3.

 

For children 5-11 years no booster doses are recommended, including in immunocompromised persons.

 

WHO EUL recommendation--Booster at 4-6 months after dose 2 with mRNA vaccine. Consider EUL vectored vaccine for 2nd primary or subsequent booster doses.

0.25 ml, (half-primary dose; 50 µg) IM 5
months after completion of primary series in persons >18 years.

 

Moderate and severe immunocompromise this is dose 4 (50 µg) to be given 3 months after dose 3. 

 

Moderna vaccine (50 µg) can be used to boost a primary series of Pfizer or Janssen/J&J vaccine in approved age groups.

 

WHO EUL recommendation--Booster at 4-6 months after dose 2 with mRNA vaccine. Consider EUL vectored vaccine for 2nd primary or subsequent booster doses.

Boost with the indicated booster dose of an mRNA vaccine in healthy persons aged ≥ 18 years, at least 2 months after a previous initial dose of Janssen/J&J. 

 

Moderate and severe immunocompromise: booster (dose 3) with an mRNA vaccine at least 2 months after the additional primary dose in previous initial Janssen/J&J vaccinees whether 1 or 2 previous Janssen/J&J doses received. 

 

WHO EUL recommendation. Booster at 4-6 months after dose 2. Consider EUL mRNA vaccine for 2nd primary or subsequent booster doses. 

Optional: Second Booster Dose (US ACIP guidelines presented; wide national variations regarding boosters)

 

(Supporting clinical data limited to short-term benefit mostly in cohorts over age 60)

Optional: 0.3 ml IM  (30 µg) in healthy persons aged >50 years, 4 months after first booster dose of either mRNA vaccine. Dose 4 for this population.

 

Optional:  0.3 ml IM  (30 µg) in moderately and severely immunocompromised persons aged ≥12, 4 months after the first booster dose of either mRNA vaccine. Dose 5 for this population.  

 

Pfizer vaccine (30 µg) can be used to boost a primary series of Moderna or Janssen/J&J vaccine in approved age groups.

 

WHO EUL recommendation--subsequent boosters not yet considered.

Optional: 0.25 ml, (half-primary dose; 50 µg) in healthy persons aged >50 years, 4 months after first booster dose of either mRNA vaccine. Dose 4 for this population.

 

Optional:  0.25 ml, (half-primary dose; 50 µg) in moderately and severely immunocompromised persons aged ≥18, 4 months after the first booster dose of either mRNA vaccine. Dose 5 for this population.  

 

Moderna vaccine (30 µg) can be used to boost a primary series of Pfizer or Janssen/J&J vaccine in approved age groups.

 

WHO EUL recommendation--subsequent boosters not yet considered.

Optional:  May choose to boost with the indicated booster dose of an mRNA vaccine in healthy persons aged ≥ 50 years, 4 months after the first booster dose whether that booster dose was mRNA or Janssen/J&J. Dose 3 in these persons.

 

Optional: Healthy persons aged 18-49 years who received the Janssen/J&J vaccine as both their primary series dose and first booster dose may receive a second booster dose using an mRNA vaccine at least 4 months after the Janssen/J&J booster dose.  Dose 3 for these persons.

 

Optional:  May choose to boost with the indicated booster dose of an mRNA vaccine in moderately and severely immunocompromised persons aged ≥18, 4 months after the first booster dose whether 1 or 2 previous Janssen/J&J doses received.  Dose 4 for this population

WHO Authorization

  • The following COVID-19 vaccines have WHO and/or other regulatory authorization
  • These vaccines also satisfy U.S. vaccination requirements for entry into the United States
  • See individual vaccine pages for complete summaries: NovavaxAstraZeneca, SinoVac, SinoPharm, Bharat
Vaccine AstraZeneca COVID-19 Vaccine 
(Vaxvevria, Covishield (India), AZD1222,
ChAdOx1).
SinoVac COVID-19 Vaccine (CoronaVac) Sinopharm/Beijing
Institute of Biological Products COVID-19 Vaccine (BBIBP-CorV)
Bharat COVID-19 Vaccine (Covaxin). FDA rejected EUA application for pediatric use. Novavax COVID-19 Vaccine (Nuvaxovid, Covovax (India), NVX-CoV2373). FDA EUA expected by Q2 2022
  See vaccine page for full details See vaccine page for full details See vaccine page for full details See vaccine page for full details See vaccine page for full details
Age ≥ 18 yrs. Trial for age 6-17 yrs currently paused. Many countries not using in adults under 60 due
to thrombosis AE.
≥ 18 yrs ≥ 18 yrs ≥ 18 yrs  ≥ 18 yrs
Type Nonreplicating chimpanzee adenovirus vector Inactivated Inactivated Inactivated  Recombinant protein subunit
Primary Dosing in adults (including immunocompromised; including additional primary dose
0.5 mL IM; 2 doses 4-12 wks apart (UK & EU) and 4 wks in US trial. 8-12 wks under WHO EUL 2 doses 14 or 28 days apart 2 doses 14 or 21 days apart 2 doses 28 days apart  2 doses 21 days apart
Booster Dosing (WHO EUL guidelines presented; wide national variations regarding boosters)

Booster at 4-6 months after dose 2. Consider EUL mRNA vaccine for 2nd primary or subsequent booster doses.

Booster at 4-6 months after dose 2. Consider EUL mRNA or vectored vaccine for 2nd primary or subsequent booster doses.  Booster at 4-6 months after dose 2. Consider EUL mRNA or vectored vaccine for 2nd primary or subsequent booster doses.  Booster at 4-6 months after dose 2. Consider EUL mRNA or vectored vaccine for 2nd primary or subsequent booster doses.  Booster at 4-6 months after dose 2. Consider EUL mRNA or vectored vaccine for 2nd primary or subsequent booster doses. 

Development Scorecard

  • Current vaccine scorecard
    • 338 candidates, 121 in clinical trials, 35 in Phase III.  27 in use in at least 1 country. Tables above list those in current use in multiple countries or with authorization from FDA, EMA, or WHO EUL.
      • All current vaccines express similar antigenic components related to the original SARS CoV-2 strain isolated in China.  Three doses of mRNA vaccines clearly induce neutralizing antibody effective against all known variants. 
      • Trials of modified vaccines to include antigenic determinants derived from the delta and omicron variants have yet to reach Phase 3 and may not do so.

Advanced Pipeline

  • A preliminary analysis (press release) indicates that 1 booster dose of a candidate adjuvanted recombinant protein vaccine targeting the original SARS-CoV-2 parent strain virus (Sanofi/GSK joint venture) given between 4 and 10 months after a complete primary vaccination schedule of another vaccine elicited a 9- to 43-fold range increase in nAbs for all age groups tested (n = 521). Results were similar whether the primary vaccine received was AstraZeneca, Janssen/J&J, Moderna, or Pfizer.
  • Some investigators believe that a heterologous boost with an inactivated vaccine after priming with either an mRNA vaccine or an adenovirus-vectored vaccine may provide a more long-term immune response (eg Novavax or Sanofi/GSK). A Phase 3 trial of this vaccine candidate as a 2-dose primary series is also underway as populations around the world are increasingly exposed to COVID-19 variants; results are expected in the first quarter of 2022.

Comments

  • Factors favoring receipt of the second booster as soon as possible (i.e., 4 months after the first booster dose):

    • Presence of underlying medical conditions (including moderately or severely immunocompromising conditions)
    • Living with someone who is vulnerable or with a vaccine contraindication
    • Living or working in or traveling to an area with a CDC community level of medium or high 
    • Increased risk of exposure to SARS-CoV-2, such as through occupational, institutional, or other activities (e.g., travel or large gatherings)

    Factors favoring delay of the second booster dose:

    • SARS-CoV-2 infection within the previous 90 days, if none of the aforementioned in-favor factors are present
    • Hesitancy about potential future booster doses; a booster dose may be more important in the fall of 2022 and/or if a variant-specific vaccine is needed.
    Special situations for compromised persons who have missed additional primary doses
    • mRNA vaccines: For persons who inadvertently received the booster dose before their third primary dose, regardless of type of vaccine received as the booster dose, administer a Pfizer vaccine or a Moderna vaccine (100 µg) as the fourth dose (third primary) at least 3 months after the third dose. 
    • Many recipients of Janssen/J&J vaccine may have received a booster dose (Pfizer, Moderna [50 µg], or Janssen/J&J vaccine), without having had the second (additional) mRNA vaccine dose. In this situation, regardless of type and timing of vaccine received as the second dose, administer a Pfizer vaccine or a Moderna vaccine (100 µg) as the third (additional) dose at least 2 months after dose 2. 
  • SARS-Cov-2 experienced persons: 
    • Prior COVID-19 infection is more protective against cases and hospitalization with Delta than 2-dose vaccination of SARS-CoV-2–naïve persons
    • Similarly,  persons who survived a previous infection had lower case rates than persons who were vaccinated alone.
    • The data suggest that natural immunity is a more potent shield than vaccines against Delta and vaccinating the previously infected with the current vaccine did not improve natural immunity against Delta.
    • These robust findings are valid for Delta in people who were infected with an earlier strain that presumably stimulated a broader range of antibodies than the narrower immunity from the current spike-protein vaccine, which is aimed at the ancestral strain SARS-CoV-2.
    • Three exposures to the spike protein of SARS-CoV-2 (n = 170) by infection-plus-vaccination–induced hybrid immunity or by triple vaccination (Pfizer) elicits superior and equivalent neutralizing immunity to all variants of concern, including Omicron. These 3 consecutive spike antigen exposures resulted in an increasing neutralization capacity per antispike antibody unit and were paralleled by stepwise increases in antibody avidity.
  • Quarantine and vaccination: 
    • No quarantine (applies to exposed persons fully up-to-date on vaccination) is recommended for the following persons, but they should test on day 5; if the test result is positive or symptoms develop, they should isolate;
      • Aged ≥ 18 years and received all recommended COVID-19 vaccine doses
      • Aged 5-17 years and completed a COVID-19 primary vaccination series
      • Any aged persons with confirmed COVID-19 within the past 90 days (positive viral test result); no test recommended on day 5.
    • Persons already in quarantine because of an exposure should not be vaccinated until quarantine is over.
  • Additional considerations
    • Antibody testing is not recommended to assess for immunity following COVID-19 vaccination or to assess the need for vaccination in an unvaccinated person;
      • no correlates of protection are available and the wide variety of antibody assays have variable targets (not all related to vaccine response) and performance. 
      • With no correlate of immunity; +ve IgG only minimally reassuring, -ve IgG unhelpful in patients whose ability to mount a B-cell response is uncertain such as transplant recipients and people on anti-B cell therapies.
    • Persons with recent (time period now undefined) documented acute symptomatic or asymptomatic SARS-CoV-2 infection should be vaccinated.
      • Risk of reinfection likely increases with time following initial infection. 
      • In acute illness, including for those who develop SARS-CoV-2 infection after the first vaccine dose but before receipt of the second dose, vaccination should be deferred until criteria for discontinuing isolation have been met
    • Currently available vaccines are not recommended for outbreak management or for post-exposure prophylaxis (vaccination to prevent the development of SARS-CoV-2 infection in a person with an exposure).
    • The majority of persons are protected by 12 days after the first dose but this single-dose immunity may well be very transient without a second dose.
    • If Dose 2 is administered no more than 4 days before the minimum (21 or 28 day) interval it is considered valid; however, a dose inadvertently administered > 4 days before the minimum interval does not need to be repeated.
    • Other non-COVID vaccines notably influenza vaccine may be administered simultaneously with or at any interval before or after any SARS-CoV-2 vaccine dose.
    • mRNA vaccines do not have a risk of modifying the vaccine recipient’s genetic makeup as mRNA does not enter cell nucleus where host DNA is located. 
      • Adenovirus vaccine DNA in the nucleus has deletions of critical genes therefore cannot replicate and cannot integrate into DNA. 
  • Further detail:  https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/

Management of COVID-19