COVID-19 vaccine; SARS CoV-2 vaccine

Introduction

COVID-19 vaccine overview

comparison of Pfizer, Moderna, Astra-Zeneca & Johnson&Johnson vaccines

Indications

• prevention of COVID-19*
  • CDC's Advisory Committee on Immunization Practices (ACIP) recommends vaccination for all persons >= 12 years unless contraindicated
  • the U.S. will end Covid-19 vaccine requirements for federal employees, contractors & international travelers on May 11, 2023
  • CDC & ACOG recommend vaccination of pregnant women
  • persons who have recovered from COVID-19 should still get the vaccine
    • CDC does not advise a particular minimum interval between SARS-CoV-2 infection & vaccination
    • persons who have recovered from COVID-19 have a stronger immune response after vaccination than those who have never been infected
  • recommended for pregnant women
    • no evidence mRNA vaccines cause spontaneous abortion
    • no evidence of adverse obstetrical or perinatal outcomes with Covid-19 mRNA vaccines
  • see Covid-19 vaccine booster for indications
  • Covid-19 vaccine booster controversy in September 2021
• reduction of SARS-CoV2 transmission
  • 3 cases/100 person years fully vaccinated (Pfizer 75%, Astra-Zeneca 25%); 12/8/2020-3/3/2021 (pre Delta variant)
  • people infected with Delta variant with ~same levels of virus in their noses regardless of vaccination status
  • some suggestion of protection of transmissibility of Delta from vaccination; however, that diminishes significantly within 3 months
• persons who develop COVID-19 despite being fully vaccinated are less infectious for contacts, who in turn are protected from infection if vaccinated
• unvaccinated persons 20-fold more likely to die from Covid-19 than vaccinated persons
• vaccination reduced post-infection risk of heart failure 55% & thrombosis 78%
• in the pre-Omicron period, vaccinatated persons had lower rates of all-cause ED visits, hospitalizations, & mortality than persons immunized by prior infection
• in the pre-Omicron period, increasing nursing home staff vaccination was associated with lower incidence of COVID-19 cases & deaths among residents & staff
  • the ancestral Covid-19 vaccine (2-dose) did not protect residents or staff during the Omicron period
• during Omicron predominance, COVID-19 hospitalization rates in Los Angeles County among unvaccinated persons were 23.0 times those of fully vaccinated persons with a booster, & 5.3 times those among fully vaccinated persons without a booster
• COVID vaccination programs saved 1.6 million lives in Europe between 2020 & 2023

* Pfizer vaccine FDA-approved for emergency use authorization Dec 11, 2020

* Moderna vaccine (Spikevax) FDA-approved for emergency use authorization Dec 18, 2020

Contraindications

• previous known severe allergic reactions to components of the vaccine (polythelene glycol) or to polysorbate (structurally related to polyethylene glycol)
  • now a caution for mRNA vaccines, but contraindication for adenovirus vaccines
• active COVID-19
• received monoclonal antibodies to SARS-CoV2 or convalescent serum within 90 days
• other vaccine within 14 days
• patients undergoing hematopoietic stem cell transplant or receiving CAR T-cell therapy
  • delay vaccination for >= 3 months to maximize vaccine efficacy
  • caregivers of these patients should be immunized when possible.
• patients with hematologic malignancies receiving intensive cytotoxic chemotherapy, such as cytarabine or anthracycline-based regimens for acute myeloid leukemia.
  • vaccination should be delayed until absolute neutrophil count recovery.
• major surgery perioperative period; vaccinate at least a few days before or after surgery

* migraine prevention, including monoclonal Ab targeting CGRP pathway or Botox is not a contraindication

* Moderna & Pfizer mRNA vaccines safe during pregnancy & breastfeeding

* safe & effective to administer Covid-19 vaccine & influenza vaccine at same time

Dosage

• current FDA-approved mRNA vaccines require 2 doses
  • 21 days for Pfizer vaccine, 28 days for Moderna vaccine
  • gap between doses can be 6 weeks
• J & J adenovirus vaccine requires a single dose

• discussion of Covid-19 vaccine booster

Adverse effects

• no significant associations between vaccination with mRNA COVID-19 vaccines & selected serious health outcomes 1-21 days after vaccination
• adverse effects signal vaccine effectiveness
  • systemic symptoms: fever/chills, myalgia, nausea/vomiting, headache, fatigue
  • local symptoms: injection site pain &/or rash
• ipsilateral axillary lymphadenopathy (13%)
  • 65% within 2 weeks after 2nd mRNA vaccine, typically < 1 cm in size
• fever, myalgia, arthalgia, headache (especially after 2nd vaccine)
• nausea, vomiting, diarrhea in 1st 72 hours
• rare allergic reactions suspected to polyethylene glycol in mRNA vaccines
  • contained in both Pfizer & Moderna vaccines
  • polyethylene glycol has never been used before in an approved vaccine
  • polyethylene glycol is found in many drugs implicated in anaphylaxis
  • allergic reactions after mRNA vaccination reported in 2% of vaccine recipients
  • anaphylaxis after mRNA vaccination reported in 2.5 of 10,000 vaccine recipients
    • 159 patients with reported 1st dose reactions to mRNA vaccine, including 19 with 1st dose anaphylaxis, tolerated a 2nd mRNA vaccine
  • severe allergic-like reactions to the Pfizer/BioNTech SARS-CoV-2 mRNA vaccine
    • in at least 8 people
    • 21 cases of anaphylaxis with 1st 1.9 million doses
      • anaphylaxis occurred with a median of 13 minutes after COVID-19 vaccination
    • cases of anaphylaxis reported after 1st dose
  • 10 cases of anaphylaxis after administration of a reported 4,041,396 1st doses of Moderna COVID-19 vaccine (2.5 cases per million doses administered)
    • in 9 cases, onset occurred within 15 minutes of vaccination
  • no deaths due to COVID-19 vaccination identified
• risk of rare neurologic complications higher after SARS-CoV2 infection than after COVID-19 vaccination
• post-vaccination syndrome "Long vax"
  • exercise intolerance (71%)
  • excessive fatigue (69%)
  • numbness (63%)
  • brain fog (63%)
  • neuropathy (63%)
• Bell's palsy with mRNA vaccines (4 cases/30,000-43,000 trial participants)
  • 3 of 4 cases in Moderna trial received vaccine; other case received placebo
  • all 4 cases in Pfizer trial received vaccine
  • not associated with Pfizer vaccine
  • sequential contralateral facial nerve palsies following Pfizer COVID-19 vaccine after first & second dose (case report)
  • annual incidence of Bell's palsy
    • general population = 15-30/100,000
    • after Covid-19 mRNA vaccination = 19/100,000
    • with Covid-19 infection = 82/100,000
  • Covid-19 vaccination triples risk of Bell's palsy, but Covid-19 infection is associated with 3-fold risk of Bell's palsy over Covid-19 vaccination
• rare cases of Guillain-Barre syndrome after adenovirus vaccine
  • Guillain-Barre variant with bilateral facial paresis
    • 11 cases reported 10-22 days after adenovirus vaccine
  • 100-130 suspected cases after J&J vaccine
  • similar increased risk not apparent with Pfizer or Moderna mRNA vaccines
    • risk of Guillain-Barre syndrome with Janssen adenovirus vaccine 9-19 times that of Pfizer or Moderna mRNA vaccines
  • 1 case of recurrent Guillain-Barre syndrome among 702 persons with prior Guillain-Barre syndrome after Pfizer vaccination
• no association between Covid-19 vaccination & sudden sensorineural hearing loss
  • reported cases less than that of the general population
  • BNT162b2 mRNA COVID-19 vaccine might or might not be associated with increased risk of sensorineural hearing loss; effect size (if any) is very small
  • no association of BNT162b2 mRNA COVID-19 vaccine with sudden hearing loss
• AstraZeneca Vaccine may be associated with more intense adverse effects than Pfizer vaccine
• delayed large local reactions reported after 1st dose of Moderna vaccine
  • delayed cutaneous reactions in 12 patients
  • reactions appeared near injection site with a median 8 days after 1st vaccine
  • 5 patients had plaques >= 10 cm in diameter
  • resolution with median of 6 days
  • cutaneous reactions in 1.9% after 1st mRNA vaccine (women > men)
    • 83% did not have cutaneous reaction with second dose
    • 2.3% with cutaneous reaction only after second dose
  • localized injection-site reactions to the COVID-19 mRNA vaccine are a delayed hypersensitivity reaction
    • may occur sooner after the second dose, but they are self-limited & not associated with serious vaccine adverse effects (in contrast to immediate hypersensitivity reactions (anaphylaxis, urticaria)
• malaise, headache, chest pain, sweating, & anxiety in 0.07% of mRNA vaccine recipients associated with hypertension as high as 220/102 mm Hg
• fainting, dizziness & other short-term reactions at vaccintation clinics due to anxiety rather than the vaccine
• ~22 cases of thrombotic thrombocytopenia (central venous sinus thrombosis or splanchnic vein thrombosis) after Astra-Zeneca vaccine, 12 after J&J (all women), 25 after Pfizer, & 5 after Moderna vaccines
  • thrombocytopenia of thrombotic thrombocytopenia is a comsumptive process whereby thrombocytopenia occurs by platelet activation of the clotting system with resultant depletion of platelets
  • antibodies to platelet factor 4 in nearly all patients
  • mortality rate high, 47% during hospitalzation
  • in patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, & heparin-induced thrombocytopenia & platelet factor 4/heparin antibodies were rare
  • suggested treatment with argatroban, danaparoid, fondaparinux, or direct oral anticoagulants +/- intravenous immune globulin +/- high-dose glucocorticoids
• risk of cerebral venous thrombosis 10-fold higher with Covid-19 infection than with Covid-19 vaccines from Astra-Zeneca, Pfizer or Moderna
• vaccination reduces post-infection risk of heart failure 55% & thrombosis 78%
• rare cases of myocarditis associated with mRNA vaccines
  • only serious confirmed adverse effect of Covid-19 mRNA vaccines
  • ~ 1 in 50,000 cases of myocarditis after 2nd vaccination
  • > 300 cases of myocarditis & pericarditis
    • more common in males than females, more common after 2nd mRNA vaccine
    • majority of cases fully resolved with rest & supportive care
  • 33 cases of myopericarditis/million vaccines (same for Covid-19 vaccines vs other vaccines)
    • pooled mortality 8/million doses (same for Covid-19 vaccines vs other vaccines)
    • risk higher in males, persons < 30 years, mRNA vaccine recipients, & after 2nd dose (vs 1st or 3rd dose)
    • risk in males < 30 years 10-fold higher than risk in females
  • 1-5 cases per 100,000 vaccinations (BNT162b2 vaccine) less than that with Covid-19 infection 11 cases per 100,000 infections
  • 20 cases of myocarditis & 37 cases of pericarditis among 2,000,287 vaccinated persons, with no deaths
  • < 2 cases of pericarditis per million vaccines administered
  • no ICU admissions for pericarditis
  • risk vastly outweighed by benefits of vaccination
  • risk 0.000845% of persons highest after the 2nd vaccination dose in adolescent males & young men
  • risk of cardiovascular complications at 18 months lower than risk from Covid-19 induced myocarditis
  • risk among Israeli military recruits 6.43 per 100,000 in the 1st week after receiving the 3rd dose
    • cases were mild & not associated with arrhythmias or heart failure
  • causal link suspected but has not been confirmed
• capillary leak syndrome associated with AstraZeneca vaccine
  • 14 reports of capillary leak syndrome
• facial neutrophilic dermatosis in 2 older men with 24 hours of Moderna mRNA vaccine with resolution in 7-10 days in both cases
• cases of POTS 90 days after vaccination
  • incidence 5 times lower than POTS after Covid-19 (long Covid-19)
• may result in statistical increase in risk of seizures in children & adolescents
  • no increased risk of seizures in the general population
• no decreases in any sperm parameter in healthy men after mRNA vaccination
• shoulder injury related to vaccine administration (SIRVA) is rare
• 17% of patients with rheumatoid arthritis experience a flare after Covid-19 vaccination
• no increase in the incidence of acute myocardial infarction, stroke, or pulmonary embolism in elderly > 75 years following BNT162b2 mRNA vaccine
• mRNA Covid-19 vaccine is not associated with appendicitis
• the strongest risk factors for adverse effects are vaccine dose
  • 2 doses of mRNA vaccine vs 1 dose (RR=3.0)
  • vaccine brand: mRNA-1273 vs BNT162b2 (RR=2.0)
  • younger age (RR per 10 years = 0.74)
  • female sex (RR=1.6)
  • prior COVID-19 infection (RR=2.2)
• in vaccine clinical trials, adverse effects were more common among vaccine recipients that among placebo recipients, but adverse effects among placebo recipients were common, including
  • 35% after 1st dose; headache 19%, fatigue 17%
  • 32% after 2nd dose
  • nocebo responses accounted for 76% of systemic adverse effects after the 1st COVID-19 vaccine dose & for 52% after the 2nd dose
• mRNA COVID-19 vaccines not linked to increased risk of adverse neonatal outcomes
• not linked to diabetes mellitus, but Covid-19 is

* Also see v-safe in Patient information

Drug interactions

• methotrexate impairs Covid-19 mRNA vaccine response
• influenza virus vaccine & Covid-19 vaccine at the same time is safe & remains without loss of effectiveness for both vaccines

• drug interaction(s) of Covid-19 vaccine with influenza virus vaccine

Mechanism of action

• virus-neutralizing antibodies induced by vaccination are protective against COVID-19 by binding to the spike glycoprotein at a few sites, usually in or near the receptor-binding domain thus preventing the virus from attaching to the its receptor (ACE2) on human cells
• most polyclonal antibodies from Covid-19 vaccines target a region in the ACE2 receptor-binding domain that includes E484
• it is not just antibodies that offer protection after vaccination
  • T-cells & memory B-cells may also offer robust, long-lasting immunity

Clinical trials

mRNA vaccine

Moderna's mRNA-1273 vaccine (Spikevax)

• Moderna's mRNA-1273 vaccine - Moderna is short for modified RNA
  • 2 100 ug doses 28 days apart
    • 25 & 50 ug doses may be as effective as 100 ug dose
  • lowers SARS CoV-2 in bronchoalveolar lavage fluid & nasal swab specimens in Rhesus macaques on days 2 through 7 & inhibits binding of virus to ACE2 receptors relative to human convalescent serum
  • Moderna's mRNA vaccine seems to prompt an immune response in older adults
  • 94.1% efficacy in preventing symptomatic Covid-19 infection, starting from 14 days after the 2nd dose
    • 92% efficacy after 1 dose based on calculations
    • 95% effective 14 days after 1 dose, benefit begins 8 days after 1 dose
    • 100 ug dose induces higher neutralizing-antibody titers than 25 ug dose
    • Moderna's mRNA vaccine also elicits a strong CD4 cytokine response involving type 1 helper T cells
    • 30,000 U.S. participants: 5 cases of COVID-19 with vaccine vs 90 cases with placebo
    • no cases of severe COVID-19 with vaccine vs 11 with placebo
    • slight decline in antibody titers 90 days after 2nd dose of vaccine
    • antibody titers at 6 months decline more in older adults than in younger adults
    • neutralizing antibody half-life estimate: 202 days for live-virus neutralization
    • 100% antispike seroconversion by day 15 following 1st dose of vaccination
    • day 57 (day 1 is 1st vaccine) IgG anti-spike protein Ab correlate with risk of breakthrough Covid-19 infection (full protection at day 42)
    • vaccine produces neutralizing antibodies against B.1.351 (Beta) & B.1.1.7 (Alpha) strains, 6-8 times lower with the B.1.351 (Beta) variant (South African variant) than with earlier variants, but still believed protective
    • neutralizing effectiveness against B.1.351 20-40 fold reduced; 9-14 fold reduced
    • neutralizing Ab titer to pseudovirus bearing B.1.351 (Beta) spike protein was 1:290 with all serum samples from vaccinated subjects neutralizing the pseudovirus albeit at relatively low (> 1:100) dilutions
    • among previously infected individuals, a single dose of either the Pfizer-BioNTech or Moderna vaccine elicited high levels of neutralizing antibodies against B.1.351
    • 2 doses of 1/4 standard dose of Moderna COVID-19 vaccine illicits long-lasting protective antibody response & virus-specific T-cells
    • a version of Moderna's vaccine designed to protect against the B.1.351 (Beta) variant has begun testing in a phase 1 trial
    • neutralizing antibodies are reduced 5- to 6-fold against the variants discovered in Brazil (P.1)
    • both mRNA vaccines likely effective against B.1.617 variant (Delta)
      • Moderna vaccine appears to be 2-fold more effective against Delta variant in preventing breakthrough infections than the Pzifer vaccine
      • no differences in complications from Delta variant with either vaccine, with similar 21-day hospitalizations, 21-day ICU admissions, & 28-day mortality
  • it is not known if the vaccine prevents asymptomatic infection or transmission of virus from asymptomatic persons to others; Pfizer vaccine does
  • vaccine remains stable at 2-8 C for 30 days
  • Moderna emergency use authorization for adult >= 18 years
    • not approved for adolescents 12-18 years or in children < 12 years

Pzifer & NioNTech BNT162b2 vaccine

• Pfizer & BioNTech announced their RNA-Based COVID-19 Vaccine BNT162b2 selected for an efficacy study in Oct 2020
• FDA panel recommends approval of Pfizer vaccine for emergency use authorization
• FDA panel ((VRBPAC)) recommends approval of Pfizer vaccine (10 ug) for emergency use authorization for children 5-11 years
• FDA approves Pfizer vaccine (10 ug) for emergency use authorization for children 5-11 years
• FDA approves Pfizer Covid-19 vaccine for persons >= 16 years August 23, 2021
  • lipid nanoparticle nucleoside-modified mRNA vaccine encoding prefusion SARS-CoV2 spike glycoprotein
  • 2 doses 30 ug 21 days apart;
    • 11-12 week dosing interval results in higher peak antibody levels
  • 95% efficacy in preventing symptomatic Covid-19 infection,starting from 7 days after the 2nd dose
  • 100% antispike seroconversion by day 21 following 1st dose of vaccination
  • 89-94% effective at preventing asymptomatic Covid-19 infection thus prevents transmission of virus from asymptomatic persons to others
  • adjusted incidence rate ratio of 0.03 for symptomatic infection & 0.10-0.14 for asymptomatic infection > 7 days after 2nd dose
  • 85-93% effective 2 weeks after one dose based on calculations from FDA documents
    • a single dose of Pfizer vaccine is 70% effective in preventing symptomatic Covid-19 in UK healthcare workers & 57-70% effective in the elderly
    • lower viral loads observed in SARS-Cov2 positive individuals 12-37 days after 1st dose of Pfizer vaccine vs unvaccinated individuals
    • effectiveness of 1 dose of BNT162b2 vaccine against symptomatic COVID-19 is 54.4%
  • one dose may be sufficient for people who have already been infected with SARS-CoV-2
    • post-vaccine symptoms more prominent with prior Covid-19 infection after first dose of Pfizer vaccine, but similar after second dose
  • a single dose of BNT162b2 vaccine may be sufficient for spike protein IgG Ab levels to protect nursing home residents with prior COVID-19 infection
  • 100% efficacy against CDC-defined severe disease 6 months after 2nd dose
  • Pfizer COVID-19 vaccine 100% effective in adolescents age 12-15 years
  • heavier, older men may mount lesser humoral immune response
  • safe & effective in adolescents
    • adolescents produce greater immune response than young adults
  • 90% of patients with solid tumors undergoing active intravenous chemotherapy are seropositive for SARS-CoV2 antispike IgG Ab after 2 doses of BNT162B2 mRNA vaccine
    • antibody titers lower than those of healthy persons, still at 92%
    • response to Moderna's mRNA vaccine similar
  • patients with hematologic malignancy may mount inadequate antibody response
    • 39% of patients with CLL mounted adequate antibody response after 2nd dose
    • patients with multiple myeloma may mount inadequate antibody response
  • stem-cell transplantation & anti CD-20 responses lower (70-73%)
  • BNT162b2 vaccination reduces SARS-CoV2 infection in pregnant women (RR=0.22)
  • may be shipped on dry ice at temperature of -70 +/- 10 degrees C
  • temporary storage units for 15 days by refilling with dry ice
  • may be stored in normal freezers
  • undiluted, thawed Pfizer vaccine vials may be stored in a refrigerator at 2-8C (35-46F) for up to 1 month
  • 2 dose vaccine may have protective benefit 10-14 days after 1st dose
  • extra vaccine doses in Pfizer-BioNTech vials (up to 6 or 7) ok to give
  • Pfizer vaccine can neutralize SARS-CoV2 carrying the U.K. N501Y mutation &/or B.1.1.7 variant
    • variants first detected in California (B.1.429), New York (B.1.526) & in the United Kingdom (B.1.1.7) neutralized by Pfizer vaccine
  • Pfizer vaccine can neutralize SARS-CoV2 B.1.351 (South African variant) with a mean neutralizing titer of 1:184 a relative reduction of 2/3 effectiveness
    • neutralizing effectiveness against B.1.351 20-40 fold reduced
    • 100% effective against symptomatic COVID-19 due to B.1.351 variant
    • B.1.351 variant may evade protection afforded by the Pfizer vaccine
    • estimated effectiveness of Pfizer vaccine against B.1.351 is 75% with 97.4% effectiveness against severe, critical or fatal disease
  • neutralizing antibodies are reduced 4- to 7-fold against the variants discovered in Brazil
  • both mRNA vaccines likely effective against B.1.617 Delta variant (India)
    • Pfizer mRNA vaccine produces lower levels of antibodies against B.1.617.2
      • Pfizer mRNA vaccine 33% effective against B.1.617.2 after 1 dose
      • all sera tested neutralize variant viruses with titers of >= 40
      • survival from Covid-19 infection provides stronger immunity against Delta variant than 2 doses of Pfizer vaccine (Israeli study)
  • 3 doses of mRNA COVID-19 vaccine, vs none or 2 doses associated with protection against both the Omicron & Delta variants, although less protection for Omicron than for Delta
  • 4th Pfizer dose with limited defense against Omicron varian
  • 2 doses 3 weeks apart of lipid nanoparticle-nucleoside-modified RNA vaccine BNT162b1 encoding a trimerized SARS-CoV2 receptor binding domain elicits high levels of antigen-binding & virus-neutralizing antibodies in adults up to 85 years of age
  • 2 mRNA vaccines BNT162b1 encoding spike protein receptor binding domain & BNT162b2 encoding full length spike protein (FDA-approved Pfizer vaccine) appear to be effective in the elderly
  • cross-clade neutralizing antibodies (SARS-CoV1 & SARS CoV2) in survivors of SARS-CoV1 immunized with Pfizer mRNA vaccine
  • Pfizer seeks FDA-approval for Covid-19 vaccine booster July 2021
    • FDA & CDC joint statement: Covid-19 vaccine booster not needed at this time
    • antibody titer decline faster in recipients of the Pfzer vaccine than in COVID-19 survivors
      • antibody titers decline by up to 40% per month in vaccinated persons, vs < 5% per month in Covid-19 convalescents
      • at 6 months, ~84% of vaccine recipients still have detectable antibody titers, whereas ~90% of Covid-19 convalescents still have detectable antibody titers after 9 months
      • spike protein antibodies may disappear 7 months after second Pfizer dose
    • overall effectiveness of Pfizer vaccine decreases from 96% to 84% after 6 months
    • a 3rd dose of Pfizer vaccine increases immune response 11 times higher than after the 2nd dose in older patients 65-85 years of age (12 people studied)
    • a 3rd dose of Pfizer vaccine increases protection against Covid-19 infection 4-fold after 10 days in adults > 60 years according to Israeli Health Ministry
      • supporting evidence largely from Israel for Pfizer vaccine
      • no evidence in U.S, or U.K. that 3rd dose of Pfizer vaccine reduces Covid-19 hospitalizations, ICU-admissions or mortality
  • breakthrough infections after Pfizer vaccine reportedly associated with low neutralizing antibody titers
  • Pfizer plans to test a COVID-19 vaccine booster targeting SARS-CoV2 B.1.351
  • CDC's ACIP supports use of Pfizer-BioNTech COVID-19 vaccine for children >= 12 years
  • Pfizer vaccine for children < 12 years of age
    • dose authorized for persons >= 12 years is 30 ug
      • effectiveness in preventing hospitalization 78% during Omicron predominance
    • dose evaluated in children age 5-11 years is 10 ug
    • Pfizer vaccine for children < 12 years of age ineffective in preventing infection in the Omicron predominance & 48% effective in preventing hospitalization
  • single case of immune thrombocytopenia (ITP) 3 days after 1st Pfizer vaccine
    • presenting platelet count: zero; patient (a 56 yo physician) died 2 weeks later)
  • 6 cases of shingles in patients with autoimmune disease after Pfizer vaccine
  • 1 case of negative spike protein serology IgG & IgM 42 days after completion of 2-dose Pfizer Covid-19 vaccine series with intervening Tdap 1 day after 1st vaccine
  • 10 deaths likely & 26 possibly attributed to Pfizer vaccine in frail elderly nursing home residents among 30,000 vaccinated
    • the causes of death were not reported

CurVac/GalaxoSmithKline (CVnCoV) mRNA vaccine

• CurVac/GalaxoSmithKline (CVnCoV) mRNA vaccine (Germany) stable a 2-8 C for 3 months
• two dose vaccine just 47% effective

About mRNA vaccine

• mRNA vaccines highly effective in preventing Covid-19 in a real world setting
• mRNA vaccines 5.5 times more effective in preventing Covid-19 than prior SARS-Cov2 infection
• mRNA vaccines reduce COVID-19 hospitalization & disease progression among vaccine breakthrough infections
• Moderna vaccine elicits a significantly higher humoral immune response than does the Pfizer vaccine (2.7-fold 6-10 weeks after 2nd dose)
• vaccine effectiveness of Moderna vaccine (95%) better than Pfizer-BioNTech (80%) or Janssen (60%) during period of Delta variant predominance
• Moderna vaccine conferred a lower risk of breakthrough Covid-19 infections & hospitalizations during the Delta variant period than the Pfizer vaccine
• vaccine effectiveness against hospitalization after 120 days 92% for Moderna vs 77% of Pfizer (march 11-August 15 2021
• risk of severe breakthrough infection less with Moderna than with Pfizer vaccine
• mRNA vaccines induce a persistent germinal centre responses B cell response, enabling the generation of robust humoral immunity*
• suggestion that mRNA vaccines continuously stimulate production of target antigen
  • without a mechanism to stop antigen production, eventual desensitization, as with allergen immunotherapy may occur
  • anti-spike protein antibody levels decline within 6 months of vaccination
  • lifetime of mRNA derived from vaccine not known but probably short
• persons with prior COVID-19 infection show high immune response after only one mRNA vaccine dose
• significant symptoms following dose 1 associated with prior SARS-CoV2 infection
• symptoms following vaccination more frequent after dose 2 & with Moderna vaccine
• among patients with solid organ transplant
  • 57% of patients receiving antimetabolites did not mount appreciable antispike Ab response after two doses of mRNA vaccine
  • 18% of patients not receiving antimetabolites did not response to two doses of mRNA vaccine
  • a 3rd dose of mRNA-1273 vaccine induced a serologic response in 49% of kidney transplant patients who did not respond after 2 doses
  • a 3rd dose of mRNA-1273 vaccine induces an immunological response in patients with solid organ transplantation
• among patients with cirrhosis, both Pfizer & Moderna mRNA vaccines associated with reduced COVID-19 infections, hospitalizations & death
• no direct evidence that glucocorticoid injection before or after administration of an mRNA COVID-19 vaccine decreases efficacy of the vaccine
  • based on expert opinion, elective glucocorticoid injection should be scheduled > 2 weeks prior to or > 1 week following mRNA vaccination
• protection against mild & moderate disease has allegedly decreased over time with decreased effectiveness of the vaccines for Delta variant playing role
• effectiveness of mRNA vaccines against hospitalization stable (92-95%)
• 2 doses of mRNA vaccine still provides significant protection against Covid-19 in immunocompromised patients, although a 3rd dose is recommended
• see Covid-19 vaccine booster for 3rd vaccinations for the general public
• small study of 27 participants finds lower levels of inhibition of spike-ACE2 binding using in vitro multiplex competitive immunoassay 2 months after 2nd mRNA vaccine
• mRNA vaccine side effects & immune responses were similar in pregnant & non-pregnant women
  • binding & neutralizing antibody responses, CD4 & CD8 T-cell responses are present in pregnant, lactating, & nonpregnant women following vaccination
  • neutralizing antibodies are also observed in infant cord blood & in breast milk
  • binding & neutralizing antibody titers against SARS-CoV2 variants B.1.1.7 & B.1.351 are reduced, but T-cell responses are preserved
• WHO says vaccines authorized for use in the United States & Europe offer protection against the four main coronavirus variants known to exist including the ones first detected in Brazil (P.1) & South Africa (B.1.351)
• MRNA vaccines from Pfizer & Moderna elicit antibodies with modest neutralization resistance against Beta, Delta, Delta plus & Lambda variants
  • in contrast, J&J adenovirus vaccine much less effective
• mRNA vaccines highly effective among healthcare workers
  • incidence of confirmed SARS-CoV2 infection is 0.19 per 1000 person days 14 days after 1st dose of Moderna or Pzifer mRNA vaccine & 0.04 per 1000 person days 14 days after 2nd dose
  • 2 women among 417 fully mRNA vaccinated persons developed Covid-19
    • viral sequencing identified variants, E484K in 1 woman & 3 mutations (T95I, del142-144, & D614G) in both (identified as alpha variant)
    • both cases were managed as outpatient
• CDC to stop investigating breakthrough COVID-19 infections
  • excepting hospitalizations or deaths
• 10,262 breakthrough infections among ~101 million fully vaccinated persons in U.S. as of April 30, 2021
• breakthrough infections identified in San Diego healthcare workders in July 2021 coincident with emergence of Delta variant & with end of California's face mask mandate
• of 555 cases available for sequencing, the B.1.1.7 variant was responsible for 56% of cases; B.1.429 in 25%; B.1.427 (another California variant) in 8%; & P.1 (Brazilian variant) in 8%
• CDC says Pfizer & Moderna mRNA vaccines may be mixed in exceptional situations & the 2nd dose can be administered up to 6 weeks after the 1st dose
• Pfizer's chief executive, Albert Bourla, promised Joe Biden that Pfizer could deliver a new mRNA vaccine effective against an 'escape variant' of SARA-CoV2 within 100 days - a prototype could be developed within a few days

* quiescent spike protein-specific bone marrow plasma cells recovered 8 months after COVID-19 infection suggesting long-lived immunity (see Covid-19 pathology section)

Adenovirus vaccine

• no direct evidence that glucocorticoid injection before or after administration of an adenovirus COVID-19 vaccine decreases efficacy of the vaccine
• based on expert opinion, elective glucocorticoid injection should be scheduled > 2 weeks prior to or > 1 week following adenovirus vaccination

Johnson & Johnson's Ad26.COV2.S vaccine

• in a phase 1 study, a single immunization with Ad26.COV2.S induced rapid binding & neutralization antibody responses as well as cellular immune responses
• in a phase 3 study a single dose of Ad26.COV2.S protects against symptomatic Covid-19 & severe-critical disease, including hospitalization & death
• a single dose induces an immune response in both younger & older persons
• at day 29 after the first dose, seroconversion rate was >= 99% in younger persons & 96% in older persons
• Ad26.COV2.S vaccine 85% effective overall in preventing severe disease & 100% effective in preventing COVID-19 related hospitalization & death as of day 28
• protection against severe disease across ages, & multiple virus variants, including B.1.351 South African variant
• single-dose of Ad26.COV2.S vaccine reduces the risk of asymptomatic transmission by 74% at 71 days compared with placebo
• J&J COVID Vaccine Gets Green Light from FDA Panel Feb 26, 2021
• WHO recommends J&J Ad26.COV2.S vaccine for adults >= 18 years
• J&J Ad26.COV2.S vaccine on hold in U.S. due to rare cases of blood clots (cerebral venous sinus thrombosis) within 6-13 days of vaccination
• ACIP gives green light for J&J vaccine for all adults
  • J&J vaccine comes with warning
• J&J Ad26.COV2.S vaccine with low neutralizing resistance against Beta, Delta, Delta plus & Lambda variants in a significant number of patients
• a 2nd dose of J&J Ad26.COV2.S vaccine induces high antibody levels
• CDC panel recommends use of Pfizer, Moderna COVID-19 vaccines over J&J shot due to blood clot risk.
• FDA severely limits use of J&J COVID-19 vaccine due to rare cases of thrombosis with thrombocytopenia syndrome

Oxford/AstraZeneca/AZD1222 adenovirus vaccine

• also ChAdOx1 nCoV-19 vaccine
• from the University of Oxford & AstraZeneca
• uses replication-deficient chimpanzee adenovirus vector
• authorized in U.K. as 2 dose vaccine give 4-12 weeks apart
• recommended & approved by the World Health Organization (WHO)
• vaccine seems to perform better when the dosing interval is longer
• 90% effective with a halved 1st dose of vaccine & a full 2nd dose
• 2 full doses only 62% effective
• a single dose has some effectiveness in the elderly
• induces neutralizing Ab & T-cell responses against SARS-CoV-2 >90% of participants within 28 days
• local & systemic reactions (chills, fever) diminished with prophylactic acetaminophen
• systemic adverse effects of fatigue, fever, headache
• rare cases of thrombotic thrombocytopenia
  • 3 cases of ischemic stroke co-occurring with thrombotic thrombocytopenia
• 76% efficacy against symptomatic infection 22-90 days after a single dose
• no hospitalizations or severe cases of COVID-19 in participants treated with AZD1222
• 79% vaccine efficacy at preventing symptomatic COVID-19 & 100% efficacy against severe or critical disease & hospitalization in U.S. study
  • NIH calls into question completeness of AstraZeneca's interim data
• may reduce transmission of COVID-19
  • 67% reduction in PCR positive swabs among those vaccinated
  • 22% efficacy against asymptomatic infection
• despite a reduction in neutralizing antibody activity, ChAdOx1 nCoV-19 vaccine is effective against SARS CoV2 B.1.1.7
• does not prevent infection of the B.1.351 variant found in South Africa
• several European countries have temporarily halted use of the AstraZeneca/Oxford COVID-19 vaccine after reports of blood clots in people recently vaccinated
• World Health Organization (WHO) & European Medicines Agency (EMA) consider benefits of the AstraZeneca vaccine to outweigh any potential risks

Sputnik V adenovirus vaccine

• Sputnik V a non-replicating adenovirus type-5 (Ad5) vectored vaccine expressing the spike glycoprotein safe & induces immune response in > 94-100% of humans
  • rAd26 & rAd5 (Sputnik V) adenovirus vaccine shows 92% efficacy in interim results from a phase 3 trial
  • safe & effective ~70 nations, but does not have WHO approval

vaccine to vaccinate the world

• Corbevax produced in India
• made through microbial fermentation in yeast
• easy to store & inexpensive
• mainly mild adverse events, perhaps one of safest COVID-19 vaccines in use
• produces higher levels of neutralizing antibodies against the Delta & Beta variants (Omicron data pending) than AstraZeneca adenovirus vaccine

inactivated SARS CoV-2 vaccine

• China National Pharmaceutical Group (Sinopharm & SinoVac) vaccines
• uses an inactivated strains of SARS CoV2 to trigger immune responses
• requires two doses
• Hebei Provincial Center for Disease Control & Prevention in Zanhuang (Hebei, China)
• CoronaVac inactivated SARS CoV-2 vaccine
  • well tolerated & safe
  • induces humoral responses in children & adolescents aged 3-17 years
  • two 3 ug doses 28 days apart
• 3 intramuscular injections at days 0, 28, & 56 of inactivated SARS CoV-2 vaccine demonstrated immunogenicity measured by a 50% plaque reduction neutralization test against live SARS-CoV-2 with low incidence of adverse reaction
• 2 inactivated SARS-CoV-2 vaccines reduced risk of symptomatic COVID-19
• serious adverse events were rare
• Covaxin is India's whole virus inactivated vaccine

protein subunit vaccine

• Novavax NVX-CoV2373 protein subunit COVID-19 vaccine FDA-approved in U.S.
• vaccine contains recombinant trimeric full-length SARS-CoV2 spike glycoproteins & Matrix-M1 adjuvant
• 2 doses 3 weeks apart
• overall efficacy 94%; 100% effective against moderate to severe disease
• 93% effective against variants of concern Alpha variant (B.1.1.7) only variant specifically mentioned
• NVX-CoV2373 Covid-19 vaccine is effective against the B.1.351 (beta) variant
• NVX-CoV2373 Covid-19 vaccine equally effective when co-administered with the influenza virus vaccine
• Sanofi-GSK vaccine is a recombinant protein subunit vaccine
• 2 dose vaccine or useful as booster
• 100% effective against severe COVID-19 & hospitalization
• 75% efficacy against moderate or severe disease.
• effectiveness against Omicron similar to Moderna & Pfizer vaccines
• investigational SARS-CoV-2 vaccine (SCB-2019) containing a trimeric form of spike protein, was immunogenic & well tolerated in a phase 1 Australian trial
• 2 IM injections 21 days apart
• stable for > 6 months at 2-8 C
• investigational adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV2 spike glycoprotein stabilised in a pre-fusion conformation by a molecular clamp
• unfortunately interferes with HIV assay

DNA vaccines

• ZyCoV-D is a DNA vaccine approved in India for adolescents (>12) & adults
• ZyCoV-D uses circular strands of DNA (plasmids) containing DNA encoding the spike protein together with a promoter to facilitate transcription in the host cell nucleus
• ZyCoV-D is administered into the skin without an injection
  • subcutaneous skin captures DNA far more efficienty than muscle
• 3 doses required
• 67% protective against symptomatic COVID-19 (Delta) in clinical trials
• stable at 77 F for at least 3 months, althouth stored at lower temperatures
• ~12 DNA vaccines against COVID-19 are in clinical trials globally

Intranasal vaccine

• mucosal vaccines may prevent even mild cases of illness & block transmission to other people, achieving sterilizing immunity
• Indian regulators approved Bharat Biotech's intranasal vaccine for emergency use on September 6, 2022
• do-it-yourself intranasal vaccine
• designed by Preston Estep, PhD (former George Church MIT grad student)
• subunit vaccine the uses peptides that match parts of SARS-CoV-2 to stimulate an immune response
• vaccine free of charge to some 70 people
• participants receive materials in the mail & must mix & administer the vaccine themselves
• two intranasal vaccines in phase 2 clinical trials
• live-attenuated influenza virus expressing spike protein of SARS-CoV-2 (China)
• protein subunit vaccine (Iran)
• two intranasal vaccines in phase 1 clinical trials in U.S.
• nonreplicating adenoviral vector vaccine produces IgA & IgG
• live attenuated virus produces mucosal IgA
• other intranasal vaccines in phase 1 clinical trials
• nasal spray version of ChadOx1 vaccine
• Codagenix/Serum Institute of India's live-attenuated SARS CoV-2 COVI-VAC vaccine
• protein subunit vaccine (Cuba)
• other intranasal vaccines
• India's Bharat Biotech's non-replicating adenoviral vector vaccine.
• China's Ad5-nCoV
• nasal spray that blocks absorption of SARS CoV2 completely protects ferrets from COVID-19 in a small study see COVID-19 Comparative biology subsection
• major advantage of intranasal vaccines would be to create a strong immune response at the initial site of virus entry, with production of mucosal secretory IgA, decreasing infectivity of human secretions & viral transmission
• intramuscular vaccines do not induce nasal mucosal antibodies
• intranasal vaccines can induce systemic immunity as well as secretory IgA throughout the respiratory system, including pulmonary alveoli
• seven intranasal COVID-19 vaccines in development
• administering the Oxford/AstraZeneca COVID-19 vaccine through the nose reduced viral shedding in animal models
• an open-label clinical trial of the intranasal vaccine in healthy human volunteers is being conducted by University of Oxford researchers
• intranasal COVID-19 vaccination with Oxford/AstraZeneca's adenovirus-vector vaccine did not induce a consistent mucosal antibody response or a strong systemic response
• unadjuvanted intranasal mRNA spike protein vaccine elicits protective mucosal immunity against SARS-Cov1 & SARS-Cov2 in mice & hamsters
• intranasal mucosal vaccines that use non-mRNA technology, including a Newcastle disease vaccine carrying the spike protein & 2 different live virus vaccines
• intranasal application of an ointment containing neomycin prevented aerosol transmission of respiratory viruses
• intranasal neomycin induces expression of multiple interferon-stimulated genes important in containing viral infections
  • this occurs independent of anti-bacterial effects of neomycin
  • in mice, activation of these genes has dose-dependent benefits for prevention & treatment of multiple variants of SARS-CoV2 & influenza A viruses
  • intranasal neomycin ointment (Neosporin) in healthy humans induces expression of multiple interferon-stimulated genes
• a Phase 1 trial of an experimental nasal vaccine may provide enhanced breadth of protection against emerging SARS-CoV-2 variants

Inhaled vaccine

• plans to start a phase I/II trial of inhaled vaccine (China)
• an inhaled version of a COVID-19 vaccine, produced by the Chinese company CanSino Biologics in Tianjin, was approved for use as a booster dose in China.

Oral vaccine

• Oravax is an oral vaccine in development
• several other oral vaccines in phase 1, 1/2 or 2 clinical trials

Vaccines in development

• mutationally constrained SARS-CoV-2 epitopes recognized by T-cells
• epitopes for use in a vaccine for T-cells to provide protective immunity

* a discussion of COVID-19 vaccines in development

putative vaccines not effective

• bacille Calmette-Guerin (BCG) not effective

Breakthrough infections

• vaccine effectiveness generally decreases over time against SARS-CoV-2 infections, hospitalizations, & mortality
• risk for breakthrough infection after Pfizer, Moderna or J&J vaccine higher in persons with substance use disorder than in general population
• risk 6.8% for tobacco use disorder, 7.8% for cannabis use disorder, higher than 3.6% in the general population
• risk higher still for cocaine (RR=2.1) vs cannabis (RR=1.9)
• risk for breakthrough infection was higher in persons with substance abuse who received the Pfizer vaccine than the Moderna vaccine

Notes

• comparison of Pfizer, Moderna & J&J vaccines
  • people vaccinated for Covid-19 with reduced all-cause mortality in the 6 months following vaccination
    • RR=0.34 (Pfizer); RR-0.31 (Moderna); RR-0.54 J&J
• injection (presumptively intramuscular) of "antibody-rich" plasma of COVID-19 survivors suggested for passive immunization lasting for months
• Russia announces approval of COVID-19 vaccine without clinical trials
• AstraZeneca temporarily halted coronavirus vaccine trials to investigate an unexpected illness in a participant
• median 2 month follow-up requirement for vaccines to receive emergency use authorization
• more Americans have received COVID-19 vaccine than have tested positive for virus
• fully vaccinated persons who meet criteria will no longer be required to quarantine following an exposure to someone with COVID-19 provided
  • received both vaccine doses, & at least 2 weeks since the 2nd dose
  • within 3 months of their last dose
  • no COVID-19 symptoms since their exposure
• CDC recommends vaccinated & boosted healthcare staff no longer quarantine after high-risk exposures
• people who have been fully vaccinated against SARS-CoV-2 can gather in small groups without masks (CDC guideline)
• 96% of practicing physicians have been fully vaccinated as of June 2021
• COVAX is the global COVID-19 vaccine distribution program
  • COVAX was established rapidly without inclusive governance or sufficient funding
  • a more robust financing mechanism could be triggered by WHO declaring a public health emergency of international concern
• since the Delta variant has become the dominant strain
  • vaccine effectiveness against hospitalization has ranged from 75%-95%.
    • for adults > 75 years, vaccine effectiveness against hospitalization is > 80% at the end of July 2021; for ages 18-49, efficacy is ~94%
  • unvaccinated adults 17 times more likely to be hospitalized than vaccinated adults
  • vaccine effectiveness against preventing infection ranges from 39%-84%
• excess mortality was higher for Republican voters than Democratic voters in Florida & Ohio after COVID-19 vaccines were available to all adults, but not before
  • differences in vaccination attitudes between Republican & Democratic may have been a factor

More general terms

• vaccine

More specific terms

• Covid-19 vaccine booster

Additional terms

• severe acute respiratory syndrome coronavirus 2; SARS-CoV2; Wuhan coronavirus

Patient information

COVID-19 vaccine patient information