ASH Guidelines: Diagnosis and Management of COVID-19 Vaccine-Induced Thrombosis with Thrombocytopenia

SUMMARY:

Although very rare, thrombosis with thrombocytopenia syndrome (TTS) has been associated with AD26.COV2.S (J&J) vaccine in the US and similar events have been documented outside the US with use of the CHaDOx1 nCov-19 (AstraZeneca) vaccine. This syndrome has been referred to by alternate names in the literature, including vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) or ‘vaccine-induced immune thrombotic thrombocytopenia (VITT)’. TTS is being used by the FDA and CDC. The American Society of Hematology has provided guidance on diagnosis and when to refer.

TTS Diagnostic Criteria

• All 4 criteria must be met
  • J&J or AstraZeneca vaccine within 4 to 30 days
  • Venous or arterial thrombosis (often cerebral or abdominal)
  • Thrombocytopenia (current TTS definition <150,000/μL)
  • Positive PF4 ‘HIT’ (heparin-induced thrombocytopenia) ELISA

Note: In early stage of TTS, thrombosis may be present prior to platelet count decrease

Clinical Findings

• Severe headache
• Visual changes
• Abdominal pain
• Nausea and vomiting
• Back pain
• Shortness of breath
• Leg pain or swelling
• Petechiae, easy bruising, or bleeding

Work-Up

Labs

1. CBC with platelet count and peripheral smear
   • Mean platelet count in published reports: 20,000/μL | There is a range from profound to mild
2. D-dimers: Most patients have significantly elevated levels
3. Fibrinogen: Some patients have low levels
4. PF4-heparin ELISA: almost all cases reported have positive assays | Most will have optical density >2.0 to 3.0

Note: Do not use non-ELISA rapid immunoassays for HIT | Non-ELISA tests are not sufficiently sensitive nor specific for TTS

Imaging for Thrombosis

• Imaging based on symptoms
• Focus on cerebral sinus venous thrombosis (CSVT) with use of CT or MRI venogram
• Patients may also have splanchnic thrombosis, pulmonary emboli, and/or DVT

Treatment

• IVIG 1 g/kg daily for two days
• Non-heparin anticoagulation
  • Parenteral direct thrombin inhibitors (argatroban or bivalrudin if aPTT is normal) or
  • Direct oral anticoagulants without lead-in heparin phase or
  • Fondaparinux or
  • Danaparoid

When to Treat

While waiting for PF4 ELISA

• Begin IV immune immunoglobin and nonheparin anticoagulation if there is clinical evidence of serious thrombosis AND ≥1 of the following
  • Positive imaging
  • Low platelets
• If PF4 ELISA returns negative and there is no thrombocytopenia, TTS is ruled out
  • Treat for venous thromboembolism using standard protocols

KEY POINTS:

• TTS is suspected
  • Obtain immediate CBC with platelet count and imaging for thrombosis based on symptoms
  • If thrombosis and/or thrombocytopenia is present, referral to hematologist with expertise in hemostasis is recommended
• Do not use non-ELISA rapid immunoassays for HIT
• Avoid heparin until TTS ruled out or other reasonable diagnosis has been established
• In addition

If thrombocytopenia but no thrombosis and negative PF4 ELISA, likely ITP

Microangiopathy with red cell fragmentation and hemolysis have not been features of reported cases, thus distinguishing this syndrome from TTP/HUS is straightforward

Avoid platelet transfusions unless other treatments have been initiated AND life-threatening bleeding or imminent surgery

Consider referral to tertiary care center if TTS is confirmed

Learn More – Primary Sources:

American Society of Hematology: Thrombosis with Thrombocytopenia Syndrome (also termed Vaccine-induced Thrombotic Thrombocytopenia)

Safety and Efficacy Data of BNT162b2 COVID-19 Vaccine

BACKGROUND AND PURPOSE: 

• BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein
  • The messenger RNA (mRNA) used in this vaccine includes the code used by SARS-CoV-2 to produce spike protein that helps the virus enter and infect cells
  • Following vaccination, the mRNA enters the vaccine recipient’s normal cells that will use the mRNA code to produce spike proteins that will generate an immune reaction
  • In the future, if the vaccine recipient is exposed to the SARS-CoV-2 virus, the antibodies generated by this immune system reaction will recognize and neutralize the invading virus
• Polack et al. (NEJM, 2020) report on the safety and efficacy of the BNT162b2 (Pfizer-BioNTech) vaccine in preventing COVID-19

METHODS:

• Ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial
• Participants
  • ≥16 years old
• Interventions
  • BNT162b2 vaccine candidate
    • 30 μg per dose
    • Two doses, 21 days apart
  • Placebo
• Study design
  • 1:1 randomization
• Primary outcome
  • Efficacy of the vaccine against laboratory-confirmed COVID-19
  • Safety

RESULTS:

• 42,448 participants were randomized and received injections
  • BNT162b2: 21,720 participants
  • Placebo: 21,728 participants
• BNT162b2 was 95% effective in preventing COVID-19
  • Placebo: 162 cases
  • BNT12b2: 8 cases (onset at least 7 days after the second dose)
  • (95% CI, 90.3 to 97.6)
• Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by
  • Age | Sex | Race | BMI | Coexisting conditions
• There were 10 cases of severe COVID-19 with onset after the first dose
  • Placebo: 9 cases
  • BNT162b2: 1 case
• Side effects
  • Mild-to-moderate pain at the injection site
  • Fatigue
  • Headache
• Fever (≥38°C): After second dose: 16% of younger vaccine recipients (16 to 55 years) | 11% of older recipients (>55 years)
  • Fever ≥38.9 to 40°C
    • After first dose: 0.2% of vaccine recipients | 0.1% of placebo
    • After second dose: 0.8% of vaccine recipients | 0.1% placebo
  • Fever >40.0°C
    • 2 participants each in the vaccine and placebo groups
• Incidence of serious adverse events was low and similar for the vaccine and placebo groups

CONCLUSION:

• Two doses of BNT162b2 spaced 21 days apart conferred 95% protection against COVID-19 in people aged 16 and over with a safety profile similar to other vaccines
• This study does not address the following populations
  • Adolescents | Children | Pregnant women
• Vaccine requires very cold temperatures for shipping and long-term storage
  • Standard refrigerators can be used for up to 5 days when ready for use
• The authors state

The data presented in this report have significance beyond the performance of this vaccine candidate

The results demonstrate that Covid-19 can be prevented by immunization, provide proof of concept that RNA-based vaccines are a promising new approach for protecting humans against infectious diseases, and demonstrate the speed with which an RNA-based vaccine can be developed with a sufficient investment of resources

Learn More – Primary Sources:

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

The Moderna Vaccine: Study Results Presented to ACIP CDC Committee

PURPOSE:

• The FDA has issued an Emergency Use Authorization (EUA) for the Moderna COVID-19 (mRNA-1273)
  • For ages ≥18 years to prevent COVID-19
  • Lipid nanoparticle-encapsulated, nucleoside-modified mRNA vaccine encoding the stabilized prefusion spike glycoprotein of SARS-CoV-2
  • 2 doses (100 μg, 0.5 mL each) administered IM 28 days apart
• The body of evidence for the Moderna COVID-19 vaccine was primarily informed by one large trial
• Oliver et al. (MMWR, 2020) on behalf of ACIP, assessed the data and report on the findings and ACIP interim recommendations 

METHODS:

• Randomized, double-blind, placebo-controlled Phase III clinical trial
• Participants
  • ≥18 years
  • Pregnant and lactating women were not included in this dataset
• Randomized 1:1 to 2 groups
  • Vaccine
  • Saline placebo
• Primary study outcome
  • Efficacy: Prevention of symptomatic, laboratory-confirmed COVID-19 among persons without evidence of previous SARS-CoV-2 infection

RESULTS:

• 30,351 enrolled participants
  • Vaccine: 15,185
  • Placebo: 15,166
• Age: 18 to 95 (median: 52 years)

Vaccine Efficacy

• The vaccine demonstrated high efficacy after 2 doses (7 week follow-up)
  • Vaccine: 11 cases
  • Placebo: 185 cases
  • Vaccine efficacy: 94.1% (95% CI, 89.3% to 96.8%)
• In this final scheduled analysis (9 week follow-up) similar results were obtained
  • Vaccine efficacy: 94.5% (95% CI, 86.5 to 97.8)
• High efficacy was observed across age, sex, race, and ethnicity categories and among persons with underlying medical conditions

Adverse Events

• Systemic adverse reactions were more commonly reported after the second dose
• More frequent and severe in persons aged 18 to 64 years than in those aged ≥65 years
• Most local and systemic adverse reactions occurred within the first 1 to 2 days after vaccine receipt and resolved in a median of 2 to 3 days
• Severe local or systemic adverse reactions (grade ≥3 reactions)
  • Occurred more commonly in vaccine recipients (21.6%) vs placebo recipients (4.4%)
  • Among vaccine recipients, 9.1% reported a grade ≥3 local injection site reaction, and 16.5% reported a grade ≥3 systemic adverse reaction
• Serious adverse events: Death | Life-threatening | Requires inpatient hospitalization or prolongation of existing hospitalization | Results in persistent disability/incapacity
  • No difference between groups (1% in both)
• No specific safety concerns were identified in subgroup analyses by age, race, ethnicity, underlying medical conditions, or previous SARS-CoV-2 infection
• Detailed summary of safety data and adverse events can be found in ‘Learn More-Primary Sources’ below

CONCLUSION:

• Based on the above data, ACIP issued an interim recommendation for the use of the Moderna vaccine
• ACIP concluded that

COVID-19 is a major public health problem and that use of the Moderna COVID-19 vaccine is a reasonable and efficient allocation of resources. Whereas there might be uncertainty about how all populations value the vaccine, it was determined that for most populations, the desirable effects outweigh the undesirable effects, making the vaccine acceptable to implementation stakeholders 

Learn More – Primary Sources:

The Advisory Committee on Immunization Practices’ Interim Recommendation for Use of Moderna COVID-19 Vaccine — United States, December 2020

Local Reactions, Systemic Reactions, Adverse Events, and Serious Adverse Events: Moderna COVID-19 Vaccine

FDA Takes Additional Action in Fight Against COVID-19 By Issuing Emergency Use Authorization for Second COVID-19 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine (NEJM)

Safety and Efficacy of AstraZeneca Oxford’s COVID-19 Vaccine

BACKGROUND AND PURPOSE:

• AstraZeneca Oxford’s ChAdOx1 nCoV-19 vaccine uses an adenoviral vector ChAdOx1 that contains the SARS-CoV-2 structural surface glycoprotein antigen
• Voysey et al. (Lancet, 2020) evaluated the safety and efficacy of the AstraZeneca Oxford’s ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials

METHODS:

• Pooled data from four ongoing blinded, randomized, controlled trials (COV001-3 are single blind | COV005 is double blind)
  • COV001: Phase 1/2; UK
  • COV002: Phase 2/3; UK
  • COV003: Phase 3; Brazil
  • COV005: Phase 1/2; South Africa
• Participants
  • ≥18 years and older
• Interventions
  • ChAdOx1 nCoV-19 vaccine
    • Standard dose/Standard dose (SD/SD) cohort: 2 doses containing 5 × 10¹⁰ viral particles
    • Low dose/Standard dose (LD/SD) cohort: Subset in the UK trial received a half dose as their first dose and a standard dose as their second dose
  • Control
    • Meningococcal group A, C, W, and Y conjugate vaccine OR saline

Note: The lower dose (LD) was noted during quality control procedures (for COV002 trial) and the protocol was amended following review and approval

• Study design
  • Analysis was according to treatment received, with a data cutoff on Nov 4, 2020
  • Vaccine efficacy was calculated as 1-relative risk derived from a robust Poisson regression model adjusted for age
• Primary outcomes
  • Primary efficacy analysis: symptomatic COVID-19 in seronegative participants with a positive PCR test >14 days after a second dose of vaccine

RESULTS:

• 23,848 participants enrolled | 11,636 were included in the interim primary efficacy analysis

Efficacy

• SD/SD vaccine efficacy: 62.1% (95% CI, 41.0 to 75.7%)
  • ChAdOx1 nCoV-19 group: 0.6% developed COVID-19
  • Control: 1.6% developed COVID-19
• LD/SD vaccine efficacy: 90.0% (95% CI, 67.4 to 97.0%)
  • ChAdOx1 nCoV-19 group: 0.2% developed COVID-19
  • Control group: 2.2% developed COVID-19
• Overall vaccine efficacy across both groups was: 70.4% (95% CI, 54.8 to 80.6%)
  • ChAdOx1 nCoV-19 group: 0.5% developed COVID-19
  • Control group: 1.7% developed COVID-19

Safety

• From 21 days after the first dose, there were 10 people hospitalized for COVID-19, all of which were in the control arm
  • Severe COVID-19: 2 participants
  • Deaths: 1 participant
• During 74,341 person-months of safety follow-up (median follow-up 3.4 months, IQR 1.3 to 4.8 months) there were 175 severe adverse events among 168 participants
  • ChAdOx1 nCoV-19 group: 84 events
  • Control group: 91 events
• 3 adverse events were classified as possibly related to the vaccine
  • ChAdOx1 nCoV-19 group: 1 participant
  • Control group: 1 participant
  • Still masked: 1 participant

CONCLUSION:

• The AstraZeneca Oxford SARS-CoV-2 vaccine, the first peer-review study of a viral-vectored coronavirus, is safe and efficacious for the prevention of symptomatic COVID-19
  • Overall efficacy was 70.4%
  • Results were generalizable across diverse settings
  • Additional benefit of a viral-vectored vaccine is the use of routine refrigerated cold chain vs ultra-low temperature freezers required for mRNA vaccines
• The authors address the increased efficacy of LD/SD dosing vs SD/SD and state

Efficacy of 90.0% seen in those who received a low dose as prime in the UK was intriguingly high compared with the other findings in the study

Although there is a possibility that chance might play a part in such divergent results, a similar contrast in efficacy between the LD/SD and SD/SD recipients with asymptomatic infections provides support for the observation

Learn More – Primary Sources:

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Comment: Oxford–AstraZeneca COVID-19 vaccine efficacy

How Common are Anaphylaxis and Allergic Reactions Following Pfizer-BioNTech COVID-19 Vaccination?

BACKGROUND AND PURPOSE:

• As of December 23, 2020, over 1.8 million first-doses of Pfizer-BioNTech’s COVID-19 vaccine had been administered in the US
• The CDC COVID-19 Response Team (MMWR, 2021) report on cases of allergic reactions, including anaphylaxis, associated with first-dose vaccination

METHODS:

• Data sources
  • Vaccine Adverse Event Reporting System (VAERS)
• Population
  • Initial vaccination was suggested for front-line healthcare workers and long-term care facility residents

RESULTS:

• Initial vaccinations: 1,893,360 first doses
  • 0.2% (n=4393) had associated adverse events
• Allergic reactions: 175 events
  • Anaphylaxis: 21 events
  • The overall anaphylaxis rate is 11.1 per million doses administered
• 17 of these events took place in persons with a documented history of allergic reactions
  • 7 of these persons had a history of anaphylaxis
• The median interval from vaccine receipt to symptom onset was 13 minutes (range 2 to 150 minutes)
• Among the 20 patients with follow-up information available, all recovered
• Of the non-anaphylaxis case reports
  • 86 were judged to be non-anaphylaxis allergic reactions
  • 61 were considered nonallergic adverse events

CONCLUSION:

• Anaphylaxis is a rare event after initial vaccination with Pfizer-BioNTech’s COVID-19 vaccine (approximately 11 per million)
• Limitations include
  • Passive reporting system which could lead to underreporting
  • Major media attention which could lead to heightened awareness and lower threshold for early treatment of suspected cases (overreporting)
• Currently, the CDC recommends vaccine providers
  • Screen for contraindications before administering the vaccine
  • Have on hand supplies needed to manage anaphylaxis, should it occur
  • Implement post-vaccination observation periods
  • Immediately treat persons who exhibit signs of anaphylaxis with intramuscular injection of epinephrine

Learn More – Primary Sources:

Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020

An Assessment of Anaphylaxis Risk Following Moderna COVID-19 Vaccination

BACKGROUND AND PURPOSE:

• As of January 10, 2021, approximately 4-million first doses of the Moderna COVID-19 vaccine have been administered in the U.S.
  • Rare cases of anaphylaxis and other allergic reactions have been reported with the Pfizer-BioNTech COVID-19 vaccine, another mRNA-based vaccine
• The CDC COVID-19 response team (MMWR, 2021) reported on cases of allergic reactions, including anaphylaxis, associated with first-dose vaccination of the Moderna vaccine

METHODS:

• Data sources
  • Vaccine Adverse Event Reporting System (VAERS)

RESULTS:

• 1266 adverse events
  • 108 case reports identified for further review for possible cases of allergic reaction, including anaphylaxis

Anaphylaxis

• Anaphylaxis cases: 10 (all women)
• Anaphylaxis rate: 2.5 cases per million doses
• Median age: 47 years (range 31 to 63 years)
• Cases with history of allergies or allergic reactions: 9
  • 5 had a history of anaphylaxis
• Median interval from vaccine receipt to symptom onset: 7.5 minutes (range 1 to 45 minutes) | 9 cases within 15 minutes
• All patients received IM epinephrine and 6 hospitalized
  • 5 ICU | 4 intubated
• Follow-up (available in 8 cases) 
  • All recovered or discharged home

Other allergic reactions and adverse events

• Other non-anaphylaxis allergic reactions
  • 43 cases within 0 to 1 day risk window
  • 60% (26/43) classified as nonserious  
  • Commonly reported symptoms: Pruritus | Rash | Itchy sensations in the mouth and throat | Sensations of throat closure | Respiratory symptoms

CONCLUSION:

• Anaphylaxis following the first dose of the Moderna vaccine is very rare, and occurred within 45 minutes of receipt with a median time of 7.5 minutes
• The CDC recommends that

Persons with an immediate allergic reaction to the first dose of an mRNA COVID-19 vaccine should not receive additional doses of either of the mRNA COVID-19 vaccines

In addition to screening for contraindications and precautions before administering COVID-19 vaccines, vaccine locations should have the necessary supplies and trained staff members available to manage anaphylaxis, implement postvaccination observation periods, immediately treat persons experiencing anaphylaxis signs and symptoms with intramuscular injection of epinephrine, and transport patients to facilities where they can receive advanced medical care

Learn More – Primary Sources:

Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Moderna COVID-19 Vaccine — United States, December 21, 2020–January 10, 2021

COVID-19 mRNA Vaccine Effectiveness in the Real World Including in Those Partially Immunized

BACKGROUND AND PURPOSE:

• Both mRNA COVID-19 vaccines (Moderna and Pfizer/BioNTech) have been shown to be effective at preventing symptomatic COVID-19 in phase III trials
• Thompson et al. (CDC MMWR, 2021) quantified SARS-CoV-2 infections among vaccinated, partially-vaccinated, and non-vaccinated essential personnel every week for 12 weeks

METHODS:

• Prospective cohort study (December 14, 2020 to March 13, 2021)
• Setting
  • Eight locations in the US
• Participants
  • Health care personnel | First responders | Other essential and frontline workers
  • No previous laboratory documentation of SARS-CoV-2 infection
• Exposure
  • Vaccination status
    • Fully immunized (≥14 days after second dose)
    • Partially immunized (≥14 days after first dose and before second dose)
    • Unvaccinated
• Study design
  • The CDC tested for SARS-CoV-2 infections
    • Every week regardless of symptom status and
    • At the onset of symptoms consistent with COVID-19–associated illness
  • SARS-CoV-2 infections were confirmed by RT-PCR
• Statistical analysis
  • Authors accounted for time-varying vaccination status
  • Results adjusted for site

RESULTS:

• 3,950 participants with no previous SARS-CoV-2 infection
  • Fully immunized: 62.8%
  • Partially immunized: 12.1%
• SARS-CoV-2 infection
  • Unvaccinated: 1.38 infections per 1,000 person-days
  • Fully immunized: 0.04 infections per 1,000 person-days
  • Partially immunized: 0.19 infections per 1,000 person-days
• Estimated mRNA vaccine effectiveness for prevention of infection
  • Full immunization: 90%
  • Partial immunization: 80%

CONCLUSION:

• Both mRNA COVID-19 vaccines are effective at preventing infection, both symptomatic and asymptomatic, in essential personnel in real world conditions
• The authors conclude

These interim vaccine effectiveness findings for both Pfizer-BioNTech’s and Moderna’s mRNA vaccines in real-world conditions complement and expand upon the vaccine effectiveness estimates from other recent studies and demonstrate that current vaccination efforts are resulting in substantial preventive benefits among working-age adults

They reinforce CDC’s recommendation of full 2-dose immunization with mRNA vaccines

COVID-19 vaccination is recommended for all eligible persons 

Learn More – Primary Sources:

Interim Estimates of Vaccine Effectiveness of BNT162b2 and mRNA-1273 COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Health Care Personnel, First Responders, and Other Essential and Frontline Workers — Eight U.S. Locations, December 2020–March 2021

An Update on COVID-19 Vaccine Related Anaphylaxis: Cases Remain Rare

BACKGROUND AND PURPOSE:

• Initial reporting rates of anaphylaxis in the US
  • Moderna: 2.5 cases per million doses (December 14 to 23, 2020)
  • Pfizer-BioNTech: 11.1 cases per million doses (December 21 to January 10, 2021)
• Shimabukuro et al. (JAMA, 2021) provide an update regarding anaphylaxis rates following vaccination

METHODS:

• Data sources
  • Vaccine Adverse Event Reporting System (VAERS)

RESULTS:

• Doses administered in US between December 14, 2020 and January 18, 2021
  • Moderna: 7,581,429 doses
  • Pfizer-BioNTech: 9,943,247 doses
• There were 66 total anaphylaxis cases after vaccine administration
  • Moderna: 19 total cases
    • Reporting rate 2.5 cases per million doses
  • Pfizer-BioNTech: 47 total cases
    • Reporting rate 4.7 cases per million doses
• Anaphylaxis case characteristics
  • Median (range) minutes to symptom onset
    • Moderna: 10 minutes (1 to 45 minutes)
    • Pfizer-BioNTech: 10 minutes (<1 minute to 19 hours)
  • Occurred in persons with a history of allergic reactions
    • Moderna: 84%
    • Pfizer-BioNTech: 77%
  • Occurred in persons with a history of anaphylaxis
    • Moderna: 26%
    • Pfizer-BioNTech: 34%
• No deaths have been reported due to vaccine-related anaphylaxis

CONCLUSION:

• Millions of doses of the Moderna and Pfizer-BioNTech COVID-19 vaccines have been administered in the US
  • Anaphylaxis is a rare event
  • The reporting rate is 2.5 (Moderna) and 4.7 (Pfizer-BioNTech) cases per million doses
• Immediate epinephrine administration is indicated for all cases of anaphylaxis
• The authors conclude

When considered in the context of morbidity and mortality from COVID-19, the benefits of vaccination far outweigh the risk of anaphylaxis, which is treatable 

Learn More – Primary Sources:

Reports of Anaphylaxis After Receipt of mRNA COVID-19 Vaccines in the US—December 14, 2020-January 18, 2021

The Value of Vaccination for Those Previously Infected with SARS-CoV-2

BACKGROUND AND PURPOSE:

• BNT162b2 (Pfizer/BioNTech) COVID-19 vaccine was shown to be 95% effective at preventing COVID-19
• Several COVID-19 variants have been detected in recent months
  • South Africa variant: B.1.351
  • UK variant: B.1.1.7
  • Brazil variant: P.1
• Lustig et al. (NEJM Correspondence, 2021) investigated whether one dose of the BNT162b2 vaccine would increase neutralizing activity against the B.1.1.7, B.1.351, and P.1 variants in people previously infected with SARS-CoV-2

METHODS:

• Microneutralization assay
• Population
  • Healthcare workers
  • Previously infected with the original SARS-CoV-2
• Study design
  • All participants were given a single dose of the BNT162b2 vaccine
  • Serum samples were obtained
    • 1 to 12 weeks after natural infection
    • Immediately before vaccination
    • 1 to 2 weeks after vaccination

RESULTS:

• 18 serum samples from 6 healthcare workers
• The sample obtained at the first time point (1 to 12 weeks after infection)
  • Had neutralizing activity against
    • The original virus: geometric mean titer 456
    • B.1.1.7 (UK): 256
    • P.1 (Brazil): 71
  • Had no neutralizing activity against
    • B.1.351 (South Africa): geometric mean titer 8
• Immediately before BNT162b2 vaccination, titers were lower against all virus variants
  • Original virus: geometric mean titer 81
  • B.1.1.7 (UK): 40
  • P.1 (Brazil): 36
  • B.1.351 (South Africa): 7
• 1 to 2 weeks after vaccination, titers were high against all virus variants
  • Original virus: geometric mean titer 9195
  • B.1.1.7 (UK): 8192
  • P.1 (Brazil): 2896
  • B.1.351 (South Africa): 1625

CONCLUSION:

• After one dose of the BNT162b2, people who had previously been infected with the original SARS-CoV-2 showed high neutralizing activity against the UK, South Africa and Brazil variants
• The authors conclude

This highlights the importance of vaccination even in previously infected patients, given the added benefit of an increased antibody response to the variants tested

Learn More – Primary Sources:

Neutralizing Response against Variants after SARS-CoV-2 Infection and One Dose of BNT162b2

Potential Pathology Behind AstraZeneca COVID-19 Vaccination and Blood Clots

BACKGROUND AND PURPOSE:

• Schultz et al. (NEJM, 2021) describes 5 cases of severe thrombosis and thrombocytopenia following vaccination with the ChAdOx1 (AstraZeneca) COVID-19 vaccine

METHODS:

• Case reports
• Setting
  • Oslo University Hospital, Norway
• Cases included
  • 5 healthcare workers
  • 32 to 54 years old
• Study design
  • Serum antibodies tested (ELISA)
    • Platelet factor 4 (PF4)-polyanion complexes
    • SARS-CoV-2 spike and nucleocapsid proteins

RESULTS:

• 4 patients had severe cerebral venous thrombosis with intracranial hemorrhage | Fatal in 3 patients
• At time of admission
  • Levels of D-dimer were elevated in all patients
  • Screening for thrombophilia with proteins C and S and antithrombin was negative
• Platelet immunologic testing
  • All five patients had high levels of IgG antibodies to PF4–polyanion complexes
  • Platelets in serum from Patients 1, 3, 4, and 5 were clearly activated in the absence of added heparin
• All patients were negative for SARS-CoV-2 antibodies, suggesting previous infection was unlikely

CONCLUSION:

• 5 individuals developed severe venous thromboembolism in unusual sites and concomitant thrombocytopenia 7 to 10 days after vaccination (AstraZeneca)
• All 5 patients had a high level of antibodies to PF4–polyanion complexes
• The authors suggest

…that these cases represent a vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia (VITT)

Learn More – Primary Sources:

Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination

Johnson & Johnson COVID-19 Vaccine: Safety and Efficacy Data from the Phase 3 Trial

BACKGROUND AND PURPOSE:

• Ad26.COV2.S, known as the Johnson & Johnson COVID-19 vaccine in the US, is a viral vector vaccine that uses an adenovirus vector encoding SARS-CoV-2 spike protein
• Sadoff et al. (NEJM, 2021) report the primary analyses of an ongoing phase 3 trial to evaluate the safety and efficacy of a single dose for prevention of COVID-19 and SARS-CoV-2 infection in adults

METHODS:

• International, randomized, double-blind, placebo-controlled, phase 3 trial
• Participants
  • Adults aged 18 to 59 years of age
  • Seronegative or unknown serostatus at the start of the study (‘per protocol’ patients)
• Intervention
  • Single dose
  • Placebo
• Primary outcomes
  • Vaccine efficacy against moderate to severe/critical COVID-19
    • Onset at least 14 days after vaccination
    • Onset at least 28 days after vaccination
  • Safety

RESULTS:

• 19,630 received vaccine | 19,691 received placebo
• Vaccine protected against moderate to severe/critical Covid-19
  • Cases with onset at least 14 days after administration
    • Vaccine group: 116 cases
    • Placebo group: 348 cases
    • Efficacy 66.9% (adjusted 95% CI, 59.0 to 73.4)
  • Cases with onset at least 28 days after administration
    • Vaccine group: 66 cases
    • Placebo group: 193 cases
    • Efficacy 66.1% (adjusted 95% CI, 55.0 to 74.8)
• Vaccine efficacy was higher against severe–critical Covid-19
  • Severe cases with onset at least 14 days after administration
    • Efficacy 76.7% (adjusted 95% CI, 54.6 to 89.1)
  • Severe cases with onset at least 28 days after administration
    • Efficacy 85.4% (adjusted 95% CI, 54.2 to 96.9)

Efficacy Against South Africa Variant (B.1.351)

• Vaccine efficacy was maintained against South Africa variant against moderate to severe/critical COVID-19
  • Moderate to severe–critical efficacy
    • Onset at least 14 days after administration: 52.0%
    • Onset at least 28 days after administration: 64.0%
  • Severe-critical efficacy
    • Onset at least 14 days after administration: 73.1%
    • Onset at least 28 days after administration: 81.7%
• Vaccine safety
  • Reactogenicity was higher with than with placebo but was generally mild to moderate and transient
  • Incidence of serious adverse events did not differ between groups
• Deaths
  • Vaccine group: 3 deaths (none related to COVID-19)
  • Placebo group: 16 deaths (5 COVID-19 related)

CONCLUSION:

• The J&J vaccine was effective at preventing  COVID-19 at least 28 days after vaccination, especially against severe/critical COVID-19
• Efficacy was still high in South Africa, where a majority of COVID-19 cases were due to the South African variant
• There were no major adverse events associated with vaccination
• There were no COVID-19 related deaths in the vaccine group

Learn More – Primary Sources:

Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19

AstraZeneca and Pfizer Side Effects and Efficacy: Real World Data from the UK

BACKGROUND AND PURPOSE:

• In phase 3 clinical trials of the Pfizer-BioNTech vaccine, injection-site pain (71 to 83%), fatigue (34 to 47%), and headache (25 to 42%) were commonly seen
• Menni et al. (The Lancet Infectious Diseases, 2021) investigate the safety and effectiveness of the Pfizer and AstraZeneca vaccines in a UK community setting

METHODS:

• Prospective observational study
• Data source
  • COVID Symptom Study app data
  • Between Dec 8 through March 10, 2021
• Population
  • General UK population 
• Exposure
  • One or two doses of the Pfizer -BioNTech vaccine
  • One dose of the AstraZeneca vaccine
  • Unvaccinated controls
• Study design
  • All analyses were adjusted by
    • Age (≤55 years vs >55 years)
    • Sex
    • Health-care worker status (binary variable)
    • Obesity (BMI <30 kg/m2 vs ≥30 kg/m2)
    • Comorbidities (binary variable, with or without comorbidities)
• Primary outcome
  • Proportion and probability of self-reported systemic and local side effects within 8 days of vaccination
• Secondary outcome
  • SARS-CoV-2 infection rates in vaccinated individuals

RESULTS:

• 627,383 vaccinated individuals
  • At least one dose of Pfizer-BioNTech: 282,103 individuals | Two doses of Pfizer-BioNTech: 28,207 individuals
  • One dose of AstraZeneca: 345,280 individuals

Systemic Side Effects

• Report rates of systemic side effects after vaccination
  • After first dose of Pfizer-BioNTech: 13.5% | After second dose of Pfizer-BioNTech: 22.0%
  • After first dose of AstraZeneca: 33.7%
• Most common systemic side effects
  • Fatigue and headache
  • Usually within first 24 hours after vaccination | Lasted a mean of 1.01 days
• Systemic side effects were more common among those with a history of previous SARS-CoV-2 infection
  • After first dose of Pfizer-BioNTech: 2.9 times more likely
  • After first dose of AstraZeneca: 1.6 times more likely
• Adverse systemic events were more common in
  • Women vs men: 16.2% vs 9.3% after first dose of Pfizer-BioNTech (OR 1.89 [95% CI, 1.85 to 1.94]; p<0·0001) and similarly after first dose of AstraZeneca
  • ≤55 years vs >55 years: 20.7% vs 10.6% after first dose of Pfizer-BioNTech (OR 2.19 [95% CI, 2.14 to 2.24]; p<0.0001) and similarly after first dose of AstraZeneca
  • Similar pattern in women and younger individuals were also noted for local side effects

Local Side Effects

• Most common local side effects
  • Tenderness and local pain around the injection site
  • Usually on the day after injection | Lasted a mean of 1.02 days
• Local side effects after vaccination
  • After first dose of Pfizer-BioNTech: 71.9% | After second dose of Pfizer-BioNTech: 68.5%
  • After first dose of AstraZeneca: 58.7%
• Local side effects were also higher in individuals previously infected with SARS-CoV-2
  • After first dose of Pfizer-BioNTech: 1.2 times more likely to experience side effects
  • After first dose of AstraZeneca: 1.4 times more likely

Vaccine Effectiveness

• SARS-CoV-2 positive tests
  • Vaccinated: 3% (3106 infections per 103,622 vaccinated)
  • Unvaccinated: 11% (50,340 infections per 464,356 unvaccinated)
• Significant reductions in infection risk were seen starting at 12 days after the first dose and increased over time
  • At 21 to 44 days
    • Pfizer-BioNTech: 69% (95% CI 66 to 72)
    • AstraZeneca: 60% (95% CI 49 to 68)
  • At 45 to 59 days
    • Pfizer-BioNTech: 72% (95% CI 63 to 79)

CONCLUSION:

• Systematic and local side effects with Pfizer and AstraZeneca COVID-19 vaccination were more common in women, individuals ≤55 years, and those with previous COVID-19 infection
• A reduction in infection risk was observed starting 12 days after the first dose for both vaccines
• The authors conclude

Localised and systemic side effects after vaccination are less common in a real-world community setting than reported in phase 3 trials, mostly minor in severity, and self-limiting

Our data will enable prediction of side-effects based on age, sex, and past COVID-19 status to help update guidance to health professionals to reassure the population about the safety of vaccines

Learn More – Primary Sources:

Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study