mRNA-Based COVID-19 Vaccines Induce Robust, Persistent Immune Responses in Humans

BACKGROUND AND PURPOSE: 

  • The mRNA-based COVID-19 vaccines are 95% effective at preventing COVID-19, but immune system dynamics induced by the vaccines are not clear 
  • Turner et al. (Nature, 2021) examined antigen-specific B cell responses in peripheral blood and lymph nodes in individuals who received 2 doses of the Pfizer vaccine 

METHODS: 

  • Observational study 
  • Participants 
    • Healthy US adults who received both doses of Pfizer’s COVID-19 vaccine 
  • Study design 
    • Blood samples were collected at baseline (before first dose), and at weeks 3 (pre-second dose), 4, 5, 7, and 15 
    • Fine needle aspirates of the draining axillary lymph nodes were also collected from some participants 
    • An enzyme linked immune absorbent spot assay was used to measure antibody-secreting plasmablasts (cells that differentiate into non-dividing plasma cells [aka antibody-secreting cells]) 

RESULTS

  • 41 adults 
    • Evidence of previous SARS-CoV-2 infection: 8 participants 
    • Aspirates collected from lymph nodes: 14 participants 
  • Circulating IgG- and IgA-secreting plasmablasts peaked one week after the second dose and then declined | Undetectable 3 weeks later 
    • Plasmablasts exhibited neutralizing activity against the early circulating SARS-CoV-2 strain and emerging variants 
    • Previously infected participants had the most robust serological response 
  • Aspirates from the draining axillary lymph nodes identified germinal center B cells that bound the SARS-CoV-2 spike protein in all participants who had received first dose 
    • The draining lymph nodes sustained high levels of spike-binding germinal center B cells and plasmablasts for at least 12 weeks after the second dose 
  • Spike-binding monoclonal antibodies derived from germinal center B cells mostly targeted the receptor-binding domain of the spike protein  
    • Fewer clones did cross-react and bind to the N-terminal domain or to epitopes shared with the spike proteins of human betacoronaviruses 
    • These cross-reactive clones had higher levels of somatic hypermutation vs those specific to SARS-CoV-2 spike protein, suggesting a memory B cell origin 

CONCLUSION

  • mRNA-based COVID-19 vaccines induce a persistent germinal center B cell response, which leads to robust humoral immunity 
  • The authors state 

To our knowledge, this is the first study to provide direct evidence for the induction of a persistent antigen-specific germinal centre B cell response after vaccination in humans 

Elicitation of high affinity and durable protective antibody responses is a hallmark of a successful humoral immune response to vaccination 

By inducing robust germinal centre reactions, SARS-CoV-2 mRNA-based vaccines are on track for achieving this outcome 

Learn More – Primary Sources: 

SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses 

Guidance on COVID-19 Vaccine Including Pregnancy

SUMMARY:

The CDC currently recommends COVID-19 vaccination for individuals 6 months and older in the United States for the prevention of coronavirus disease 2019 (COVID-19). Vaccination during pregnancy and lactation period is encouraged to mitigate the significant risks associated with COVID.

SMFM recommends that pregnant, postpartum, and lactating people and those
considering pregnancy receive the COVID-19 vaccination

Vaccination is the best method to reduce maternal and fetal complications of SARS-CoV-2 infection

Counseling to support the recommendation for vaccination should include available data on vaccine efficacy, as well as data on vaccine safety during pregnancy and lactation

Provider counseling has been shown to have a significant positive impact on patient vaccination

Counseling Points

  • The SMFM document refers clinicians to the CDC recommendations (links can be found in ‘Learn More – Primary Sources’ below)
  • CDC recognizes pregnant women are at risk for severe health effects from COVID-19 and recommends COVID-19 vaccination during pregnancy
    • While a conversation with a healthcare provider may be of benefit, it is not a requirement prior to vaccination
  • Counseling should include the following elements
    • Available data on vaccine safety
    • Discussion about limited data regarding fetal risk
    • Pregnant patients have higher risk of moderate to severe disease
    • Level of COVID-19 community transmission

Maternal And Obstetric Risk 

  • With symptomatic COVID-19, pregnancy is an independent risk factor compared to symptomatic non-pregnant patients for
    • ICU admission: 3-fold increase
    • Mechanical ventilation
    • ECMO: 2 to 4 fold increase
    • Death: 1.7 fold increase
    • May increase preterm birth and stillbirth
  • Other risk factors for severe COVID-19 disease include
    • Cancer | Chronic kidney disease | COPD | Heart conditions | Immunocompromised state | Sickle cell disease | Smoking
  • Hispanic or Latinx and Black patients are disproportionally affected by higher prevalence of COVID-19
    • More severe maternal morbidity | Higher risk of death

Vaccine Mechanism

  • Three COVID-19 vaccines are currently available in US | None are live vaccines

mRNA Vaccines (Pfizer | Moderna)

  • Contain mRNA for SARS-CoV-2 spike S protein
    • Pfizer-BioNTech BNT162b2
    • Moderna mRNA 1273 vaccines
  • Two-dose vaccine (Pfizer 3 weeks apart; Moderna 4 weeks apart)

Adenoviral-Vector Vaccine (Janssen Biotech Ad26.COV2.S; Pharmaceutical company of Johnson & Johnson)

  • One-dose vaccine
  • Adenovirus carries the gene for the coronavirus spike S protein, which is then produced by the host cell
    • The presence of spike protein on the host cell’s membrane will induce an immunogenic response

Note: Due to increased risk for thrombosis with thrombocytopenia syndrome (TTS), the FDA has limited the authorized use of the Janssen COVID-19 Vaccine to (1) individuals 18 years of age and older for whom other authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, and (2) to individuals 18 years of age and older who elect to receive the Janssen COVID-19 Vaccine because they would otherwise not receive a COVID-19 vaccine

Considerations for Administration

  • Pregnancy test prior to vaccination is not recommended
  • No need to delay pregnancy following vaccine administration
  • No trimester-specific indications at this time

Efficacy

mRNA Vaccines

  • Optimal efficacy 1 to 2 weeks after second dose
  • Pfizer-BioNTech: 95.0% (95% CI, 90.3% to 97.6%)
  • Moderna: 94.1% (95% CI, 89.3% to 96.8%)

Johnson & Johnson Adenoviral-Vector Vaccine (Janssen Biotech)

  • 1 time dose
  • 72% effective at preventing moderate to severe disease
  • 85% effective at preventing severe disease
  • 100% effective at preventing COVID-19–related hospitalization and death 28 days after vaccination

Primary Series Dosing

  • Pfizer-BioNTech: 2-dose primary series
    • 5 to 11 years: 10 µg dose | 3 weeks apart
    • ≥12 years: 30 µg dose | 3 to 8 weeks apart
  • Moderna: 2-dose primary series
    • 6 to 11 years: 50 µg | 4 to 8 weeks apart
    • ≥12 years: 100 µg | 4 to 8 weeks apart
  • Janssen: Single dose primary series
    • ≥18 years: 5×1010 viral particles

Primary Series for Children From 6 Months Through 5 Years of Age

  • Pfizer (6 months through 4 years)
    • 3 primary doses are recommended
    • 3 µg per dose (1/10 adult dose)
    • Interval between 1st and 2nd dose: 3 to 8 weeks
    • Interval between 2nd and 3rd dose: At least 8 weeks
  • Moderna (6 months through 5 years)
    • 2 primary doses are recommended
    • 25 µg per dose (1/4 adult dose)
    • Interval between 1st and 2nd dose: 4 to 8 weeks

Note: Spacing between first and second can be up to 8 weeks with both Pfizer and Moderna vaccines (CDC) | Although absolute risk for myocarditis associated with mRNA vaccine is small, some studies suggest that among adolescents and adults, the risk for myocarditis may be reduced and peak antibody responses and vaccine effectiveness may be increased with an interval longer than 4 weeks | Original interval is still recommended for “people who are moderately or severely immunocompromised; adults ages 65 years and older; and others who need rapid protection due to increased concern about community transmission or risk of severe disease”

COVID-19 Vaccines for People who are Moderately or Severely Immunocompromised

  • CDC has specific recommendations for COVID vaccine schedules for individuals who are moderately or severely immunocompromised | See ‘Learn More – Primary Sources’ for the most current information for the most current schedules
  • Children ages 5 through 11 years
    • Should receive a primary series of 3 doses of Pfizer-BioNTech COVID-19 vaccine
    • Additional booster not recommended at this time
  • People 12 years
    • Should receive a total of 4 doses of mRNA COVID-19 vaccine to stay up to date
    • The 4 doses include a primary series of 3 doses of Pfizer-BioNTech or Moderna COVID-19 vaccine plus 1 booster of Pfizer-BioNTech or Moderna COVID-19 vaccine (4th dose)
    • Only Pfizer-BioNTech COVID-19 vaccine is available for teens ages 12 to 17 years
  • Moderate or severe immunocompromising conditions that include (but not limited to)
    • Active treatment for solid tumor and hematologic malignancies
    • Receipt of solid-organ transplant and taking immunosuppressive therapy
    • Receipt of CAR-T-cell therapy or hematopoietic cell transplant (HCT) (within 2 years of transplantation or taking immunosuppression therapy)
    • Moderate or severe primary immunodeficiency (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome)
    • Advanced or untreated HIV infection (people with HIV and CD4 cell counts <200/mm3, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)
    • Treatments: High-dose corticosteroids (i.e., ≥20 mg prednisone or equivalent per day when administered for ≥2 weeks) | Alkylating agents, antimetabolites | Transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive | Tumor necrosis factor (TNF) blockers | Other biologic agents that are immunosuppressive or immunomodulatory

Booster (CDC)

Pregnant women can receive any of the currently FDA-approved or FDA-authorized COVID-19 vaccines as a booster dose

Adults ≥18 years

  • Following Pfizer or Moderna mRNA primary vaccine series
    • mRNA COVID vaccine ≥5 months after completion of primary mRNA vaccine series
    • Moderately or severely immunocompromised: ≥3 months after the final dose in the primary series
  • Following Pfizer or Moderna mRNA primary vaccine series
    • mRNA COVID vaccine ≥5 months after completion of primary mRNA vaccine series
    • Moderately or severely immunocompromised: ≥3 months after the final dose in the primary series

Note: Considered ‘up to date’ immediately after getting 1st booster

Children and teens ages 12 to 17 years

  • For most children and teens: Pfizer COVID vaccine 5 months after the final dose in the primary series
  • For moderately or severely immunocompromised children and teens: 3 months after the final dose in the primary series

Note: Considered ‘up to date’ immediately after getting 1st booster

Children 5 to 11 years

  • CDC recommends a booster dose 5 months after completion of a primary series with the Pfizer-BioNTech COVID-19 Vaccine

Second Booster Dose (CDC)

  • 12+ years who are moderately or severely immunocompromised may choose to receive a second booster dose using an mRNA COVID-19 vaccine ≥4 months after the first booster dose
  • 50+ years and older who are not moderately or severely immunocompromised may choose to receive a second booster dose using an mRNA COVID-19 vaccine ≥4 months after the first booster dose
  • 18 to 49 years who are not moderately or severely immunocompromised and who received Janssen COVID-19 Vaccine as both their primary series dose and booster dose may receive a second booster dose using an mRNA COVID-19 vaccine ≥4 months after the first Janssen booster dose

Fetal Considerations

  • Limited data | Preclinical studies have been reassuring
  • mRNA vaccines
    • Available data suggests low risk
    • Rapid degradation (approximately 10 to 20 days)
    • Does not enter the cell’s nucleus or become integrated into the DNA; therefore, “no risk of genetic modification to people receiving the vaccine”
  • Adenovector vaccines
    • Available data suggests low risk
    • Viral DNA is not integrated into the host’s DNA
    • Other adenovirus vector vaccines (Ebola, HIV, and RSV) showed no adverse pregnancy outcomes
  • Maternal antibodies cross the placenta | May provide neonatal protection

CDC Adverse Event Data

  • V-safe
    • CDC “smartphone-based tool that uses text messaging and web surveys to provide personalized health check-ins” that can be used by an individual to report side effects following COVID-19 vaccination
    • Women continue to enroll in CDC’s v-safe COVID-19 Vaccine Pregnancy Registry | No serious safety signals have been identified thus far (see ‘Learn More – Primary Resources’ and ‘Related ObG Topics’ below)
    • Reactogenicity (expected inflammatory response to vaccination) and adverse events did not raise any concerns regarding increased risk for maternal or neonatal complications
  • Vaccine Adverse Event Reporting (VAERS)
    • Miscarriage was highest pregnancy related adverse event
    • Rates around 15% in keeping with normal background
  • General findings from current available data
    • No pattern suggesting of safety issue  
    • Vaccine reactions are usually mild to moderate
      • Occur within the first 3 days and  resolve within 1 to 2 days
      • Most often symptoms occur after second dose
      • Acetaminophen can be used to treat fever
    • Allergic reactions: rare (2.5 to 4.7 per million)

Lactating Persons

  • Vaccination is recommended for lactating persons
  • Counseling should provide balance with respect to lack of data vs the patients’ individual risk for infection and severe disease
  • Although there is a lack of data “the theoretical risks regarding the safety of vaccinating lactating people do not outweigh the potential benefits of the vaccine”

Antibody Titers in Pregnancy

  • Studies have demonstrated vaccine-induced antibody titers to be similar in pregnant women compared to nonpregnant women
  • Transfer of antibodies to newborns following maternal vaccination may confer neonatal protection
    • Vaccine-induced IgG is transferred to the neonate
    • Higher umbilical cord blood titers are associated with longer time intervals from vaccination
    • Second vaccine dose increases cord blood IgG levels

KEY POINTS:

  • The COVID-19 vaccine should be offered to pregnant and lactating patients
  • Providers should discuss individual risks and benefits of the vaccine during pregnancy
  • Safety profile from the CDC Adverse Event Monitoring site shows no increased risk of worse pregnancy outcomes post-vaccination with more data to be published
  • Coadministration with other vaccines: The CDC states

COVID-19 vaccines and other vaccines may now be administered without regard to timing

This includes simultaneous administration of COVID-19 vaccine and other vaccines on the same day, as well as coadministration within 14 days

It is unknown whether reactogenicity of COVID-19 vaccine is increased with coadministration, including with other vaccines known to be more reactogenic, such as adjuvanted vaccines or live vaccines

When deciding whether to coadminister another vaccine(s) with COVID-19 vaccine, providers should consider whether the patient is behind or at risk of becoming behind on recommended vaccines, their risk of vaccine-preventable disease (e.g., during an outbreak or occupational exposures), and the reactogenicity profile of the vaccines

Learn More – Primary Resources

SMFM: Provider Considerations for Engaging in COVID-19 Vaccine Counseling With Pregnant and Lactating Patients

CDC: Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States

CDC At-A-Glance COVID-19 Vaccination Schedules

CDC: COVID-19 Vaccine Booster Shots

CDCD: COVID-19 Vaccines for People who are Moderately or Severely Immunocompromised

CDC: v-safe COVID-19 Vaccine Pregnancy Registry

CDC: COVID-19 Vaccine Monitoring Systems for Pregnant People

CDC: Vaccine Adverse Event Reporting System (VAERS)

Coronavirus (COVID-19) Update: FDA Limits Use of Janssen COVID-19 Vaccine to Certain Individuals

FDA: Coronavirus (COVID-19) Update: FDA Expands Eligibility for Pfizer-BioNTech COVID-19 Vaccine Booster Dose to Children 5 through 11 Years

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

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

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)

mRNA COVID-19 Vaccine Safety in Pregnant Women

BACKGROUND AND PURPOSE:

  • The clinical trials for mRNA-based COVID-19 vaccines did not include any pregnant women, so safety data in this group was initially limited
    • However, many pregnant women in the general population have since received these vaccines, providing a cohort in which to assess safety data
  • Shimabukuro et al. (NEJM, 2021) reported preliminary findings regarding mRNA COVID-19 vaccine safety in pregnant persons from three U.S. vaccine safety monitoring systems

METHODS:

  • Setting
    • United States
    • Data from December 14, 2020, to February 28, 2021
  • Data sources
    • The “V-safe after vaccination health checker” surveillance system
    • The V-safe pregnancy registry | Telephone-based survey collects detailed information
    • The Vaccine Adverse Event Reporting System (VAERS)
  • Primary outcomes
    • Non–pregnancy-specific adverse events
    • Pregnancy- and neonatal-specific adverse events

Note: Pregnancy and neonatal outcomes were derived from patients who enrolled in the registry

RESULTS:

  • 35,691 v-safe participants self-identified as pregnant
    • Majority of the participants were
      • Between 25 to 34 years of age | Non-Hispanic White (approximately 75%)
  • 3958 participants were enrolled in the registry

Vaccine-related side effects (V-safe)

  • Injection-site pain was reported more frequently among pregnant women than among nonpregnant women
  • The following were reported less frequently among pregnant women
    • Headache
    • Myalgia
    • Chills
    • Fever

Pregnancy Outcomes

  • 827 participants completed pregnancy
    • Live birth: 86.1%
    • Spontaneous abortion: 12.6%
    • Stillbirth (0.1%)
    • Other outcomes (induced abortion and ectopic pregnancy): 1.2% 

Neonatal Outcomes

  • Preterm birth: 9.4%
  • Small for gestational age: 3.2%
  • There were no neonatal deaths

Adverse Events (VAERS)

  • 221 reports
    • Nonpregnant related: 70.1%
    • Pregnancy related: 29.9%
  • Most frequently reported pregnancy-related adverse events
    • Spontaneous abortion (37 first trimester, 2 second trimester, 7 unknown or not reported)
    • No congenital anomalies (EUA reporting requirement)

CONCLUSION:

  • While not directly comparable, the proportions of adverse outcomes in vaccinated women were similar to those reported in studies involving pregnant women before the pandemic
  • Further longitudinal study is important, especially in women vaccinated in the first trimester
  • The authors conclude that

Early data from the v-safe surveillance system, the v-safe pregnancy registry, and the VAERS do not indicate any obvious safety signals with respect to pregnancy or neonatal outcomes associated with Covid-19 vaccination in the third trimester of pregnancy

Learn More – Primary Sources:

Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons

Does COVID-19 Vaccination in Breastfeeding Women Produce Detectable Levels of Antibodies in Breast Milk?

BACKGROUND AND PURPOSE:

  • Breastfeeding women were not included in COVID-19 vaccine trials, so there are limited data on vaccine-related safety in this group
  • Perl et al. (JAMA, 2021) investigated whether maternal immunization led to detection of SARS-CoV-2 antibodies in breast milk

METHODS:

  • Prospective cohort study
  • Setting
    • Israel, between December 23, 2020, and January 15, 2021
  • Participants
    • Breastfeeding women (exclusive or partial)
    • Elected to be vaccinated
  • Exposure
    • All participants fully vaccinated with Pfizer-BioNTech vaccine
  • Study design
    • Participants were recruited through advertisements and social media
    • Breast milk samples were collected
      • Before administration of the vaccine
      • Once weekly for 6 weeks starting at week 2 after the first dose
    • IgG and IgA antibody levels were assessed
    • Weekly questionnaires coupled to breast milk collection asked participants for information about interim well-being and vaccine-related adverse events
  • Primary outcomes
    • Presence and levels of SARS-CoV-2 antibodies in breast milk

RESULTS:

  • 84 women | 504 breast milk samples
    • Women: mean age 34 years
    • Infants: mean age 10.32 months
  • Mean levels of SARS-CoV-2- IgA antibodies in breast milk increased rapidly and remained elevated throughout follow-up
    • 2 weeks after first dose: 61.8% of samples tested positive
    • 4 weeks after first dose: 86.1% of samples tested positive
    • 6 weeks after first dose: 65.7% of samples tested positive
  • IgG antibodies remained low for the first 3 weeks, with an increase at week 4, which remained high throughout follow-up
    • 4 weeks after first dose: 91.7% of samples tested positive (P=0.004)
    • 5 and 6 weeks after first dose: 97% of samples tested positive
  • Adverse events were experienced by a majority of women, but were generally mild, with local pain being the most common complaint
    • Reported events after the first dose: 55.9% of women
    • Reported events after the second dose: 61.9% of women
  • No mother or infant experienced any serious vaccine-related adverse event
  • Four infants developed a fever after maternal vaccination

CONCLUSION:

  • Both IgA and IgG SARS-CoV-2 antibodies were detected in breast milk of vaccinated mothers
    • IgA presence was evident as early as 2 weeks after the first vaccine dose
    • IgG spiked 4 weeks after the first dose
    • IgA and IgG levels remained elevated throughout the follow-up period
  • No major adverse events in mothers or infants were reported
  • The authors conclude

Antibodies found in breast milk of these women showed strong neutralizing effects, suggesting a potential protective effect against infection in the infant 

Learn More – Primary Sources:

SARS-CoV-2–Specific Antibodies in Breast Milk After COVID-19 Vaccination of Breastfeeding Women

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

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

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

Vaccines in Pregnant and Lactating Women: Is Immune Response Similar to that of Non-Pregnant Patients?

BACKGROUND AND PURPOSE:

  • Gray et al. (AJOG, 2021) evaluated the immunogenicity (ability to provoke an immune response) and reactogenicity (ability to provoke expected adverse reactions) of COVID-19 mRNA vaccination in pregnant and lactating women vs non-pregnant controls

METHODS:

  • Prospective cohort study
  • Participants (≥18 years)
    • Pregnant or nursing
    • Non-pregnant and of reproductive age
  • Exposure
    • COVID-19 vaccine (Pfizer or Moderna mRNA vaccine)
  • Study design
    • SARS-CoV-2 IgG, IgA and IgM were quantified in sera and breastmilk
    • Timepoints: Baseline | Second vaccine dose | 2 to 6 weeks post second vaccine | Delivery
    • Titers compared to those of pregnant women 4 to 12 weeks following natural infection (ELISA platform used)
    • Neutralizing antibody titers were evaluated for a participant subset who delivered
    • Post-vaccination symptoms were assessed via questionnaire
    • Differences between groups was assessed, including using statistical tools to account for multiple sampling

RESULTS:

  • 131 vaccine recipients | Cord blood obtained from 10 deliveries
    • Pregnant: 84
    • Lactating: 31
    • Non-pregnant: 16
  • Compared to non-pregnant women, pregnant and lactating women had similar vaccine-induced antibody titers (p=0.24)
    • Pregnant: Median (IQR) 5.59 (4.68 to 5.89]
    • Lactating: Median (IQR) 5.74 (5.06 to 6.22)
    • Non-pregnant: Median (IQR) 5.62 (4.77 to 5.98)
  • All vaccine-induced titers were significantly higher than those induced by natural SARS-CoV-2 infection during pregnancy (p<0.0001)
  • Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples
    • IgG breast milk levels rose concurrently with maternal serum levels
  • While neutralizing antibody titers were lower in umbilical cord vs maternal sera, the difference was not statistically significance (p=0.05)
    • Umbilical cord sera: median (IQR) 52.3 (11.7 to 69.6)
    • Maternal sera: 104.7 (61.2 to 188.2)
  • Second vaccine dose increased SARS-CoV-2-specific IgG but not IgA, such that IgG was the dominant serum antibody for all groups by 2 weeks post-second vaccine
  • Reactogenicity was similar across pregnant, lactating and non-pregnant groups

CONCLUSION:

  • Pregnant and lactating women who received either of the COVID-19 mRNA vaccines experienced robust vaccine-induced immunity
    • Immunogenicity and reactogenicity in pregnancy were similar to that seen in non-pregnant women
  • The vaccine-induced immunity response was significantly greater than the immune response caused by natural SARS-CoV-2 infection
  • Immune transfer to neonates could occur via breastmilk or placenta
  • While the authors are clear that this study does not address possible fetal risks, they conclude

While the absolute risk of severe COVID-19 is low in pregnant women, pregnancy is a risk factor for severe disease

These data provide a compelling argument that COVID-19 mRNA vaccines induce similar humoral immunity in pregnant and lactating women as in the non-pregnant population

Learn More – Primary Sources:

COVID-19 vaccine response in pregnant and lactating women: a cohort study