COVID-19, Vaccines

by David Freedman last updated Jul 21, 2023 10:14 AM © Antimicrobial Therapy, Inc.
COVID-19 Vaccines, Vaccination Schedules

Introduction

  • Data for and against need for annual vaccination against SARS-CoV still under study and FDA/ACIP guidelines are due at the end of September 2023.
    • Only XBB 1.5 containing monovalent vaccines from Pfizer & Moderna (mRNA) and Novavax (adjuvanted protein) will be recommended for use beginning in the fall of 2023.
    • Likely, further boosters will be recommended for older and high-risk persons with a personal choice option for others.
  • CDC’s latest recommendations (May 12, 2023) are that monovalent (original) mRNA vaccines are no longer recommended in the US (and are no longer available).
  • Almost the entire US population already has antibody against SARS-CoV-2 from previous infection or vaccination.
    • Unvaccinated individuals need only to receive a single dose of a bivalent vaccine, rather than multiple doses of the original monovalent mRNA vaccines. 
  • A single additional bivalent vaccine dose for adults >65 years and 1 or more additional doses for people who are immunocompromised are now recommended.
    • The updated FDA EUA states that most immunocompromised persons who have received a bivalent COVID-19 vaccine may receive a single additional dose of a bivalent vaccine >2 months following a dose of a bivalent vaccine, and additional doses may be administered at the discretion of, and at intervals determined by, their healthcare provider.
  • All persons >6 yrs should receive a bivalent mRNA vaccine, regardless of previous completion of a monovalent primary series.
  • Persons  >6 yrs who have already received a bivalent mRNA vaccine need no further doses unless they are >65 years or immunocompromised.
  • Dosing for the moderately and severely immunocompromised remains complex (see table below) despite efforts to simplify the general immunization regimens.
  • Novavax remains monovalent only.
    • Novavax remains authorized for use as a 2-dose primary series and as a booster dose in certain very limited situations.
    • The Novavax booster dose (only if no previous boosters) must be administered >6 mos after a primary series of COVID-19 vaccine.
  • See below and individual vaccine page for vaccine doses, efficacy, adverse effects, and mix and match dosing: see Pfizer, Moderna, Novavax, AstraZeneca
  • Janssen/J&J vaccine is no longer produced, no longer approved for use, and no longer included in ACIP guidelines. 
    • Persons ages 18 years and older who received the primary series dose are recommended to receive 1 bivalent mRNA vaccine dose (Moderna or Pfizer-BioNTech) at least 2 months after completion of the primary series dose (for people who have not previously received any booster doses), or at least 2 months after the last monovalent booster dose.

Indications for Vaccination (US)

  • All US persons age >6 mos should be vaccinated regardless of a history of symptomatic or asymptomatic SARS-CoV-2 infection, presence of long COVID, or history of a SARS-Cov2 breakthrough infection. 
  • Defer vaccination until recovery from acute episode and discontinuation of isolation.
    • After SARS-CoV-2 infection may consider delaying of next dose by 3 mos from symptom onset or positive test.
  •  For normal hosts:
      • Persons age >6 months should receive >1 dose of bivalent mRNA vaccine.
      • Persons age >6 yrs who are unvaccinated or previously received only monovalent vaccine doses are recommended to receive 1 bivalent mRNA vaccine dose
      • However persons >65 years may receive 1 additional bivalent mRNA vaccine dose.
  • CDC schedule for immunocompromised persons (see Immunocompromised, HIV below).

U.S. CDC COVID-19 Vaccination Schedules

  • See Pfizer COVID Vaccine and Moderna COVID-19 Vaccine for <12 years of age schedule.
  • In general, persons should receive the age-appropriate vaccine product and dosage based on their age on the day of vaccination in accordance with the recommended intervals for that age group; certain 4 and 5 yr olds present exceptions.
  • Normal Persons (not moderately or severely immunocompromised).
  • Abbreviated, non-comprehensive CDC infographic
COVID-19 vaccination history Bivalent vaccine Bivalent doses indicated Dosage (mL/ug) Interval between doses
Unvaccinated Moderna 1 0.5 mL/50 ug NA
Unvaccinated Pfizer BioNTech 1 0.3 mL/30 ug NA
1 or more doses monovalent mRNA (no doses bivalent mRNA) Moderna 1 0.5 mL/50 ug >8 weeks after last monovalent dose
1 or more doses monovalent mRNA (no doses bivalent mRNA) Pfizer BioNTech 1 0.3 mL/30 ug >8 weeks after last monovalent dose
Ever received 1 dose bivalent mRNA (regardless of monovalent vaccine history) NA; previously received 1 bivalent vaccine dose NA NA NA
  • Persons age 65 years and older have the option to receive 1 additional bivalent mRNA vaccine dose >4 months after the first dose of a bivalent mRNA vaccine. If Moderna is used, administer 0.5 mL/50 ug; if Pfizer is used, administer 0.3 mL/30 ug

EMA-approved COVID-19 Vaccines

  • EMA-approved vaccines (non-FDA approved)
    • VidPrevatyn (Sanofi;GSK), monovalent adjuvanted protein vaccine based on the Beta Variant, is EMA approved (>18 yrs) to be given once as boosters for persons given mRNA or adenovirus vaccines.  
      • Wait >4 mos after a previous vaccine dose.
  • Complete list of EMA Approved Covid-19 Vaccines

WHO-approved COVID-19 Vaccines

Efficacy, Duration of Protection

  • Time since most recent COVID-19 vaccine dose is likely more important than cumulative number of doses.
  • With continued viral evolution, after the primary series and the critical first booster, each booster dose stands on its own in inducing high VE against hospitalization for 3-6 mos.
  • Bivalent boosters provide additional moderate increased VE (vs previous monovalent booster doses only) against hospitalization from current strains for approximately 3 months.
  • Against hospitalization
    • VE against omicron BA.4.6, BA.5, BQ.1, and BQ.1.1:  
      • Against severe infection over d 15 to 99 after receipt of one monovalent booster dose, VE was 25.2% (during Q2 2022) and the corresponding VE for one bivalent booster dose was 58.7% (during Q4 of 2022)(N Engl J Med, Jan 25, 2023, online ahead of print).
        • VE equal in >65 yr group vs 12-64 yrs of age.
  • Against symptomatic infection
    • 4 doses of monovalent mRNA vaccine (compared to 3 doses; no 4th dose) has VE drops which drops from ~50% at 2 wks post dose 4 to ~35% at 3 mos.
    • Children <5 yrs VE of ~40% for primary series against symptomatic infection, wanes after 4 mos. Moderna > Pfizer
    • Relative VE (versus monovalent booster) of bivalent booster against symptomatic infection at 4-5 months since booster:  41%, 28%, 21% for age 18-49, 50-64, >65 respectively
  • Meta-analysis on protection by previous infection and hybrid immunity.  Lancet DOI:https://doi.org/10.1016/S0140-6736(22)02465-5

Choice, Interchangeability

  • People ages >6 yrs years  who previously received 1 or more doses of a monovalent mRNA vaccine may receive either bivalent Moderna or bivalent Pfizer vaccine.
    • See individual vaccines pages for younger children..
  • Pre-Omicron data indicate that the Moderna vaccine has both a VE and durability advantage over the Pfizer vaccine (higher mRNA dose in monovalent doses)

Toxicities

Contraindications

  • See individual vaccine pages
  • Recent exposure to SARS-CoV-2 is not a contraindication or precaution to COVID-19 vaccination.

Precautions

  • See individual vaccine pages
  • Recent SARS-CoV-2 infection may allow consideration of delaying a primary series dose or booster dose by 3 mos
    • Increased interval may improve immune response to vaccination.
  • Administration of an antiviral drug pre- or post-vaccination unlikely to impair response

Adverse Effects

  • See individual vaccine pages for minor adverse effects.
  • Safety similar whether monovalent or bivalent vaccine is used as a 4th dose (2nd booster).
  • Myocarditis: 131 myocarditis cases reported to VAERS after 123 million mRNA booster vaccinations.
    • Risk primarily in adolescent and young adult males
    • No increase in children ages 5–11 yrs following 1st booster
    • Rates are lower following 1st booster dose vs. dose 2 of primary series (and lower following dose 1 vs. dose 2 of primary series)
    • An 8-wks interval between the first and second primary series doses of Moderna, Novavax, and Pfizer COVID-19 vaccines may be optimal to reduce myocarditis.
  • No safety signals for ischemic stroke with mRNA vaccines with primary doses or monovalent boosters in US or any other country.
  • One small cluster of ischemic stroke after a bivalent booster in persons >65 at a single reporting site in 1 of several US CDC and Pfizer surveillance networks needs further investigation.  
    • Possible association with concomitant adjuvanted influenza vaccine needs study prior to 2023-24 flu season.

Drug Interactions

  • Influenza (including HD or adjuvanted) and COVID-19 vaccines to be given at the same visit, if eligible.
  • COVID-19 vaccines may be administered without regard to timing of other vaccines.
  • Dose 2 administered no more than 4 d before the minimum (21 or 28 d) interval is valid; however, do not repeat an inadvertent dose administered earlier
  • No minimum interval between COVID-19 vaccination and monkeypox vaccine
  • Consider waiting 4 wks after monkeypox vaccination before COVID-19 vaccination to minimize myocarditis

Special Populations

Pregnancy, Breastfeeding

  • Vaccinate according to standard recommendations if pregnant, breastfeeding, attempting or contemplating conception.
    • Pregnant and recently pregnant persons at increased risk for severe illness and the fetus is at increased risk
  • Benefits outweighs risks of vaccination.
  • Vaccine antibodies are transferred to the newborn and likely are effective for up to 6 mos.
  • No contraindications to breastfeeding.

Moderately or Severely Immunocompromised, HIV

Ages 12 and up

COVID-19 vaccination history Bivalent vaccines # Bivalent doses indicated Dosage (mL/ug) Interval between doses
Unvaccinated Moderna† 3 0.5 mL/50 ug Dose 1 & Dose 2: 4 weeks
Dose 2 & Dose 3: >4 weeks
Unvaccinated Pfizer BioNTech‡ 3 0.3 mL/30 ug Dose 1 & Dose 2: 4 weeks
Dose 2 & Dose 3: >4 weeks
1 dose monovalent Moderna Moderna† 2 0.5 mL/50 ug Dose 1: 4 weeks after monovalent dose
Dose 1 & Dose 2: >4 weeks
2 doses monovalent Moderna Moderna† 1 0.5 mL/50 ug >4 weeks after last monovalent dose
3 doses monovalent Moderna Moderna 1 0.5 mL/50 ug >8 weeks after last monovalent dose
3 doses monovalent Moderna Pfizer BioNTech 1 0.3 mL/30 ug >8 weeks after last monovalent dose
3 doses monovalent Moderna and 1 dose bivalent mRNA NA See footnote NA NA
1 dose monovalent Pfizer Pfizer BioNTech‡ 2 0.3 mL/30 ug Dose 1: 3 weeks after monovalent dose
Dose 1 & Dose 2: >4 weeks
2 doses monovalent Pfizer Pfizer BioNTech‡ 1 0.3 mL/30 ug >4 weeks after last monovalent dose
3 doses monovalent Pfizer Moderna 1 0.5 mL/50 ug >8 weeks after last monovalent dose
3 doses monovalent Pfizer Pfizer BioNTech‡ 1 0.3 mL/30 ug >8 weeks after last monovalent dose
3 doses monovalent Pfizer and 1 dose bivalent mRNA NA See footnote NA NA
  • Footnotes
    • Immunocompromised persons ages >12 yrs  have the option to receive 1 additional dose of Moderna  (0.5 mL/50 ug); or Pfizer (0.3 mL/30 ug; gray cap ) >>2 months following the last recommended bivalent dose. Further additional dose(s) may be administered, informed by clinical judgement and personal preference and circumstances > 2 months after the last vaccine dose.
    • ‡Pfizer-COVID-19 Vaccine is also authorized in this age group with this vaccination history (0.3 mL/30 ug).
    • †Moderna COVID-19 Vaccine is also authorized in this age group with this vaccination history (0.5 ml/50 ug).
  • If possible, COVID-19 vaccines should be administered >2 wks before initiation or resumption of immunosuppressive therapies.
  • Persons with HIV not at higher risk of severe disease after completing vaccination.
    • Severe disease risk higher if CD4<350 even with vaccination;  ensure up to date with bivalent boosting. 
  • NCCN recommends against Novavax in active cancer patients unless no choice.
  • Self-attestation to moderately or severely immunocompromised status is acceptable.
  • New immunocompromise after a 2-dose primary series, no additional primary doses;  immunocompromised schedule for the booster dose
  • Revaccinate HCT or CAR-T-cell therapy recipients with an mRNA vaccine or Novavax >3 mos after HCT or CAR-T-cell therapy 
  • Consider revaccination if 1 or more doses of vaccine (primary series and bivalent booster doses) received during short-course treatment with B-cell-depleting therapies (e.g., rituximab, ocrelizumab)  begining at about 6 mos after completion of therapy.
  • Administration of vaccines should not be delayed in patients on ongoing immunosuppressives.
  • Administer vaccine doses approximately 4 wks before the next scheduled therapy for patients on ongoing B-cell-depleting therapies
  • Tixagevimab/cilgavimab (EVUSHELD™) no longer recommended as prophylaxis.
  • On a case-by-case basis, providers may administer Moderna, Novavax, and Pfizer vaccines outside of the FDA and CDC dosing intervals using a risk-benefit approach together with clinical experience and judgement. 
  • 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 assays vary widely.
  • +ve IgG only minimally reassuring, -ve IgG unhelpful in patients whose ability to mount a B-cell response is uncertain.
  • If antibody testing is done, vaccination should be completed as recommended regardless of the antibody test result.
  • Prior receipt of a COVID-19 vaccine will not affect the results of SARS-CoV-2 viral tests (nucleic acid amplification or antigen tests).

Comments

  • 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.
  • Vaccine pipeline (WHO)
  • See also