RCT Results: Do Text Message Reminders Increase Cardiovascular Medication Adherence for Nonadherent Patients?

BACKGROUND AND PURPOSE:

• Text message reminders are used to encourage medication adherence, but it’s not clear whether they actually help
• Ho et al. (JAMA, 2024) compared different types of text messaging strategies with usual care to improve medication refill adherence among patients nonadherent to cardiovascular medications

METHODS:

• Patient-level randomized pragmatic trial
  • 3 health care systems in Colorado
• Participants
  • Adults with ≥1 cardiovascular condition and ≥1 prescribed medication to treat the condition who had a 7-day refill gap
• Interventions
  • Generic reminders: generic text message refill reminders
    • e.g. “You are due to refill your [drug name]”
  • Behavioral nudge: text refill reminders incorporating behavioral nudges, with invitation to reply
    • e.g. “Hi [name]. We noticed you haven’t refilled your [drug name]. Reply 1= I’ll get them refilled in the next 2 days. Reply 2=I’m still working on a plan to get this done.”
  • Behavioral nudge + chatbot: text refill reminders plus a fixed-message chatbot
    • As above, chatbot asked about common barriers to adherence
  • Usual care
• Study design
  • Randomization stratified by health care system and number of baseline medications
  • Text messages delivered in either English or Spanish (patient preference)
  • Patients had option to reply with questions | Response by clinical pharmacists
  • If no cell phone (9% of participants): interactive voice response automated telephone calls
• Primary outcome
  • Refill adherence: proportion of days covered at 12 months
• Secondary outcomes
  • Emergency department visits
  • Hospitalization
  • Mortality

RESULTS:

• 9501 patients
  • Mean age: 60 years | Female: 47% | Black: 16% | Hispanic: 49%
• At 12 months, there were no significant difference between text message groups and usual care in mean proportion of days covered (P=0.06)
  • Generic: 62.3%
  • Behavioral nudge: 62.3%
  • Behavioral nudge + chatbot: 63.0%
  • Usual care: 60.6%
• After adjustment, there was still no significant difference (P<0.05/3 after multiple testing corrections) in mean proportion of days covered with intervention vs usual care
  • Generic reminder
    • 2.2 percentage points higher (95% CI, 0.3 to 4.2) | P=0.02
  • Behavioral nudge
    • 2.0 percentage points higher (95% CI, 0.1 to 3.9) | P=0.04
  • Behavioral nudge + chatbot
    • 2.3 percentage points higher (95% CI, 0.4 to 4.2) | P=0.02
• There were no differences in clinical events between study groups

CONCLUSION:

• Text messages reminding nonadherent patients to refill their cardiovascular medications did not increase adherence compared to usual care
• The authors state

Text message reminders were not effective in improving refill adherence at 12 months, regardless of the type of message, generic reminders, behavioral nudges, or behavioral nudges + chatbot

Learn More – Primary Sources:

Personalized Patient Data and Behavioral Nudges to Improve Adherence to Chronic Cardiovascular Medications: A Randomized Pragmatic Trial

Does Meeting Physical Activity Recommendations Reduce Mortality Risk Equally Across Age Groups?

BACKGROUND AND PURPOSE:

• The guidelines for minimum physical activity levels needed to maintain a healthy lifestyle are the same for adults of all ages
• Martinez-Gomez et al. (JAMA Network Open, 2024) explored whether there is an age-dependent association between physical activity and all-cause mortality

METHODS:

• Cohort study (4 population-based prospective cohorts)
  • National Health Interview Survey (1997 to 2018) | UK Biobank (2006 to 2010) | China Kadoorie Biobank (2004 to 2008) | Mei Jau (1997 to 2016)
• Exposure
  • Self-reported leisure-time physical activity
  • Age group
• Study design
  • Cox proportional hazards regression models with stratification by study were used to calculate mortality hazard ratios
• Primary outcome
  • Death

RESULTS:

• 2,011,186 individuals
  • Mean age: 49.1 (SD, 14.3 | Range, 20 to 97) years
  • Women: 55.0%
  • Median follow-up: 11.5 (IQR, 9.3 to 13.5) years
• The association between physical activity and mortality in the total sample showed a nonlinear dose-response pattern
• Physical activity was consistently associated with a lower risk of mortality across all age groups
  • The reduction in risk was greater in older vs younger age groups, especially at high levels of physical activity
  • Age modified this association (P_interaction<0.001)
  • Greatest reduction in risk in older adults was observed at physical activity levels 4 to 5 times higher than current recommendations
• Overall mortality hazard with recommended physical activity
  • Hazard ratio (HR) 0.78 (95% CI, 0.77 to 0.79)
• Meeting physical activity levels was positively associated with modifiable risk factors
  • High educational level | Not smoking |Healthy body weigh | No hypertension | No diabetes
  • Age modified the associations of these modifiable health factors with mortality (all P_interaction<0.001)
  • The magnitude of associations was greater in younger vs older age groups

CONCLUSION:

• Meeting physical activity recommendations was associated with reduced mortality risk throughout adulthood
• The benefit of physical activity may actually increase slightly with age
• Other modifiable health factors such as not smoking also reduced mortality, but unlike physical activity their benefit decreased with increasing age
• The authors state

In this pooled analysis of cohort studies, the association between PA and mortality risk remained consistent across the adult lifespan. This contrasts with other modifiable health factors, including educational level, smoking, alcohol consumption, body weight, hypertension, and diabetes, where we observed that their associations with mortality risk diminished with age

Given these findings, the promotion of regular PA is essential at all stages of adult life

Learn More – Primary Sources:

Physical Activity and All-Cause Mortality by Age in 4 Multinational Megacohorts

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)

COVID-19 and Coagulopathy: ISTH Issues Guidance on Diagnosis and Management

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date

SUMMARY:

The ISTH released guidance on the recognition and management of coagulopathy in the setting of COVID-19. The ISTH emphasizes the term ‘interim’ as the medical community continues to learn more about the clinical course of those infected with SARS-CoV-2. The stated goal of this guidance is

…to provide a risk stratification at admission for a COVID‐19 patient and management of coagulopathy which may develop in some of these patients, based on easily available laboratory parameters

Recommended Labs at Admission (decreasing order of importance)

D-dimers

• Consider hospital admission for patients with markedly raised D-dimers even in absence of other severity symptoms
  • “Arbitrarily defined as three-four fold increase”
  • High levels indicate increased thrombin generation

Note: This guidance does not address pregnancy specifically | D-dimer is elevated in normal pregnancy (see ‘Learn More – Primary Sources’ below)

Prothrombin time (PT)

• Current literature is demonstrating mild prolongation of PT at admission in ICU vs non-ICU cohorts (e.g., 12·2 s vs 10·7 s; Huang et al. Lancet, 2020)
• Caution: Such “subtle changes” will not be as readily identified if PT is reported as INR

Thrombocytopenia

• Unlike typical sepsis, thrombocytopenia at admission for COVID-19 was not as strong an indicator of sepsis mortality
• The authors state that “thrombocytopenia at presentation may be but not consistent prognosticator”

Monitoring Coagulation Markers

• Monitor D-dimers, platelet count, PT and fibrinogen to identify worsening coagulopathy
  • Worsening parameters: “More aggressive critical care support is warranted” including consideration of ‘experimental’ therapies and blood product support
  • Stable or improving parameters: Provides “added confidence for stepdown of treatment if corroborating with the clinical condition”

DIC

• Importance of regular laboratory monitoring
  • Day 4: In one study (Tang et al. J Thromb Haemost, 2020), DIC was much more likely to develop on day 4 among nonsurvivors vs survivors (71.4% vs 0.6%)
• Days 10 and 14: Statistically significant increase in D-dimer levels, and PT, and decrease in fibrinogen levels were likewise seen in nonsurvivors

KEY POINTS:

Management Points

• Inhibition of thrombin generation may reduce risk for multi-organ failure in the setting of sepsis

Prophylactic LMWH

• “Should be considered in ALL patients (including non-critically ill) who require hospital admission for COVID-19 infection, in the absence of any contraindications (active bleeding and platelet count less than 25 x 109 /L)”
• Monitor closely if severe renal impairment is present
• “Abnormal PT or APTT is not a contraindication”
• Additional benefits of LMWH include
  • VTE prevention
  • Anti-inflammatory properties

Parameter Thresholds

• Non-bleeding patients: Maintain
  • Platelet count >20 x 109/L
  • Fibrinogen >2.0 g/L
• Bleeding patients (rare in setting of COVID-19): Maintain
  • Platelet count >50 x 109/L
  • Fibrinogen >2.0 g/L
  • PT ratio <1.5 (note: not the same as INR)

Other therapies to manage coagulopathy

• Should be considered experimental, for example
  • Antithrombin supplementation | Recombinant thrombomodulin | Hydroxychloroquine

Lancet Haematology – Expert Opinion

Hospitalized Patients (Severe COVID-19)

• Closely monitor patient for coagulopathy: Repeat every 2–3 days
  • D-dimer
  • PT
  • Platelet counts
• Administer subcutaneous LMWH for all hospitalized patients
  • Evidence to support this practice in severe COVID-19 | “In view of the hypercoagulable state of patients with severe COVID-19, and the potential increased risk of thrombosis, we suggest that all patients with COVID-19 that are admitted to hospital should receive this prophylactic treatment in the absence of medical contraindications”
• Be on alert for VTE
  • Consider VTE in the setting of rapid respiratory deterioration and/or high D-dimer concentrations
  • CT angiography or ultrasound of the venous system of the lower extremities

Note: If diagnostic testing is not possible and there are no bleeding risk factors, consider therapeutic anticoagulation | Experimental therapies such as plasma exchange, or administration of other anticoagulants or anti-inflammatory drugs should only be undertaken via clinical trials

Learn More – Primary Sources:

ISTH interim guidance on recognition and management of coagulopathy in COVID‐19

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China (Huang et al. Lancet 2020)

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia (Tang et al. J Thromb Haemost, 2020)

D-dimer During Pregnancy: Establishing Trimester-Specific Reference Intervals

Coagulation abnormalities and thrombosis in patients with COVID-19 (Lancet Haematology Expert Comment)

Critical Care Medicine: Coagulopathy of Coronavirus Disease 2019

COVID-19, ACE Inhibitors and ARBs: Professional Guidance and Evidence Update

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date

SUMMARY:

Coronavirus disease 2019 (COVID-19) is an infection caused by the SARS-CoV-2 virus. The virus is known to target the angiotensin converting enzyme 2 (ACE-2) co-receptor. Therefore, concern has been raised whether the use of common medications that impact ACE and the renin angiotensin system may also result in increased COVID-19 infection risk. Papers have now been published demonstrating no increased risk with use of ACE inhibitors or angiotensin receptor blockers (ARBs).

• High Risk Groups for COVID-19 infection
• ACE Enzymes
• ACE Inhibitors and ARBs
• What We Currently Know about SARS-CoV-2 Infectivity
• Do ACE Inhibitors and ARBs Increase Risk for COVID-19
• Recommendations

High Risk Groups for COVID-19 infection

• Patients at higher risk for significant morbidity and mortality from COVID-19 infection include older patients, especially those with chronic medical conditions such as the following
  • Pulmonary disease
  • Cardiac disease
  • Kidney disease
  • Diabetes
  • Hypertension
• It is unclear whether the above associations are independently related to pathogenesis, other associated comorbidities, or even treatment
  • These disorders themselves are not necessarily independent and often appear together in patients, particularly in the context of the metabolic syndrome
• ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19

Angiotensin Converting Enzymes

• ACE-1 and ACE-2 are two major enzymes found in the renin-angiotensin system
  • ACE enzymes play a critical role in the balance of peptides in the angiotensin family
  • ACE-2 is found on
    • Epithelial cells in both respiratory and GI tracts
    • Cardiac and kidney cells

ACE Inhibitors and ARBs

• ACE inhibitors and ARBs
  • Strongly influence angiotensin peptides
  • Increase ACE-2 activity in cardiac tissue

What We Currently Know about SARS-CoV-2 Infectivity

• SARS-CoV-2 is covered with crown-like glycoprotein spikes (hence ‘corona’) comprised of 2 subunits
  • Subunit S1: Binds to ACE-2 on the cell surface
  • Subunit S2: Fuses with the cell membrane
  • TMPRSS2 (host enzyme): Promotes cellular entry of the virus

Do ACE Inhibitors and ARBs Increase Risk for COVID-19?

• ACE inhibitors, ARBs and other renin angiotensin aldosterone system (RAAS) inhibitors are commonly used in patients who would be considered ‘at risk’ for COVID-19
• Theoretical risk raised
  • Because ACE inhibitors and ARBs ‘may’ increase expression of ACE-2 leading to greater risk for virus to enter and infect cells, could these medication lead to increased risk for COVID-19 morbidity and/or mortality?
• Possible benefit
  • Study from China showed that while hypertension is a risk factor for COVID-19 mortality, patients on ACE inhibitors and ARBs did better (see review in ‘Learn More – Primary Sources’ below)
  • Underlying mechanism is unclear, but there may be a biphasic pattern: (1) In phase 1, these medications could increase infectivity (2) In phase 2, ACE-2 downregulation by the virus may be the “hallmark” of COVID-19 progression and therefore medications that upregulate in the second phase may be of benefit
  • In addition, there is a hypothesis that ACE-2 also stimulates one of the angiotensin peptides (angiotensin-(1-7)) that has positive anti-inflammatory effects | Therefore, medications that stimulate ACE-2 could have a beneficial effect

Current Evidence

• Zhang et al. (Circ Res, 2020)
  • Retrospective, multi-centered study | 1128 hospitalized patients with COVID-19 | ACE Inhibitors/ARB group: 188
  • After adjustment, detected risk for all-cause mortality was lower in the ACE Inhibitors/ARB group compared to the non-ACE Inhibitors/ARB group
  • Adjusted hazard ratio: 0.42 (95% CI, 0.19 to 0.92; p = 0.03)
  • These medications may be associated with a lower risk of all-cause mortality in the setting of COVID-19 compared to non-users
• Reynolds et al. (NEJM, 2020)
  • 12,594 tested | 5894 patients positive for COVID-19 | Severe in 17%
  • Hypertension history: 34.6% of tested patients | 59.1% were COVID-19 positive had a positive test | Severe in 24.6%
  • Authors conclude that there was no association with likelihood of a positive test or severity of illness
• Mancia et al. (NEJM, 2020)
  • Population-based case–control study | 6272 patients with confirmed SARS-CoV-2 infection
  • Use of ARBs or ACE inhibitors did not show any association with Covid-19 overall or those with severe or fatal disease
• Editorial (Jarcho et al. NEJM, 2020)
  • The accompanying editorial recognizes limitations inherent in observational data
  • However, these studies support professional guidance that recommend against altering these medications when indicated
  • Furthermore, the editorial authors state

Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe Covid-19 among those infected, or the risk of in-hospital death among those with a positive test. 

KEY POINTS:

Recommendations

• Guidance is based on the current lack of evidence that ACE inhibitors or ARBs increase risk of infection or result in a more severe course of COVID-19 disease
  • It is acknowledged that new data may result in a future update to these guidelines
• Professional recommendations do not support stopping or changing medications for patients who are currently being treated with ACE inhibitors or ARBs
• In addition, cessation is associated potential for significant harms including
  • Medical risk: Exacerbation of underlying medical conditions
  • Infection risk: Due to increased pharmacy encounters, visits for blood work etc.
• The HFSA/ACC/AHA recommends

…continuation of RAAS antagonists for those patients who are currently prescribed such agents for indications for which these agents are known to be beneficial, such as heart failure, hypertension, or ischemic heart disease

In the event patients with cardiovascular disease are diagnosed with COVID-19, individualized treatment decisions should be made according to each patient’s hemodynamic status and clinical presentation

Therefore, be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice

Learn More – Primary Sources:

Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19 (Vaduganathan et al., NEJM)

Drugs and the renin-angiotensin system in covid-19 (BMJ)

HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19

COVID-19: An ACP Physician’s Guide and Resources

European Medicines Agency: EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic

British Society for Heart Failure (BHF) and British Cardiology Society (BCS): Statement on ACI Inhibitors and ARBs in COVID-19

Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19 (Zhang et al. Circ Res, 2020)

Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19 (Reynolds et al. NEJM, 2020)

Renin–Angiotensin–Aldosterone System Blockers and the Risk of Covid-19 (Mancia et al. NEJM, 2020)

Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19 (Editorial. NEJM 2020)

COVID-19 Testing: CDC Guidance on Virus and Antibody Testing

• Summary
  • Specimen Collection
  • How is SARS-CoV-2 RNA Testing Performed?
  • Diagnostic Testing
  • Screening Testing
  • How Early Will a Test Be Positive?
  • Performance of RT-PCR Viral Tests
• Antibody Testing
  • General CDC Antibody Guidance
  • What Are the Different Types of Antibody Tests?
  • When Can Antibody Testing be Helpful?
  • Vaccination and Test Interpretation
• Learn More – Primary Sources

NOTE: Information and guidelines may change rapidly. Check in with listed references in ‘Learn More – Primary Sources’ to best keep up to date.

SUMMARY:

The CDC has provided guidance on both viral testing for SARS-CoV-2 as well as the role of antibody testing. Testing for the presence of the virus during the pandemic remains the current diagnostic standard. While antibody testing can play a role for public health teams to understand the spread of the disease, currently its use as a diagnostic test for individuals remains limited. A COVID-19 vaccine will not affect the results of SARS-CoV-2 viral tests.

Viral Testing

Specimen Collection

• Obtain an upper respiratory specimen for initial diagnostic testing
  • A nasopharyngeal (NP) specimen collected by a healthcare professional  or
  • An oropharyngeal (OP) specimen collected by a healthcare professional  or
  • A nasal mid-turbinate swab collected by a healthcare professional or by a supervised onsite self-collection (using a flocked tapered swab)  or
  • An anterior nares (nasal swab) specimen collected by a healthcare professional or by onsite or home self-collection (using a flocked or spun polyester swab)  or
  • Nasopharyngeal wash/aspirate or nasal wash/aspirate (NW) specimen collected by a healthcare professional
• Lower respiratory tract specimens
  • Collect and test sputum in patients who develop a productive cough | Induction of sputum is not recommended
  • Under certain clinical circumstances (e.g., those receiving invasive mechanical ventilation), a lower respiratory tract aspirate or bronchoalveolar lavage sample should be collected and tested as a lower respiratory tract specimen

How is SARS-CoV-2 RNA Testing Performed?

RT-PCR

• Usually performed using real-time reverse transcription polymerase chain reaction (RT-PCR)
  • Qualitative detection of RNA
• Multiple tests on the market that can target various genes
  • Envelope (env) | Nucleocapsid (N) | Spike (S) | RNA-dependent RNA polymerase (RdRp) | ORF1
• A positive test can only determine presence of SARS-CoV-2 RNA and not whether the virus is intact and capable of infecting others

Antigen

• Antigen tests can quickly detect fragments of proteins found on or within the virus by testing samples collected from the nasal cavity using swabs
• The benefit of antigen testing is speed, with results potentially available within minutes
• However, antigen tests, while very specific for the virus, are not as sensitive as molecular PCR tests
  • Positive antigen results: Highly accurate but higher chance of false negatives | Negative antigen results may still need PCR confirmation prior to treatment decisions or to prevent inadvertent spread of SARS-CoV-2

Note: Prior receipt of a COVID-19 vaccine should not affect the results of SARS-CoV-2 viral tests (NAAT or antigen)

Breath Sample Analysis

• FDA has issued an emergency use authorization (EUA) for a diagnostic test that detects chemical compounds in breath samples associated with a SARS-CoV-2 infection
• Test is performed by a qualified, trained operator under the supervision of a health care provider licensed or authorized by state law to prescribe tests
• Results available in <3 minutes

Diagnostic Testing

Signs or Symptoms of COVID-19

• Positive test
  • NAAT: Indicates infection regardless of vaccine status
  • Positive antigen test result may need confirmatory testing if the person has a low likelihood of SARS-CoV-2 infection (e.g., no known exposure to a person with COVID-19 within the last 14 days or is fully vaccinated or has had a SARS-CoV-2 infection in the last 3 months)
  • Isolate if positive test: Discontinue isolation 5 days after symptom onset and at least 24 hours after the resolution of any fever (without the use of fever-reducing medications) | Continue to wear mask around others for 5 additional days
    • Some individuals may require extended isolation and precautions (e.g., severely immunocompromised)
    • Testing is not recommended to determine when infection has resolved
    • Loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation​
• Negative test
  • If symptoms are consistent with COVID-19, may be a false negative | Isolation and further discussion with healthcare professional recommended

Testing to determine resolution of infection

• May be appropriate for severe illness or immunocompromise
• “For all others, a test-based strategy is no longer recommended except to discontinue isolation or precautions earlier than would occur under the symptom-based strategy”

Screening Testing

No Symptoms and No Close Contact with Someone Known to Have a COVID-19 Infection

• Asymptomatic or presymptomatic infection contribute to community SARS-CoV-2 transmission
  • May help with re-opening of businesses, communities, and schools
• Point-of-care tests (e.g., antigen tests) can be particularly helpful due to short turn-around times
• Quarantine not required while results are pending
• Examples of screening programs
  • Testing employees in a workplace setting
  • Testing students, faculty, and staff in a school or university setting
  • Testing a person before or after travel

How Early Will a Test Be Positive and How Long Until Negative?

• In patient with COVID-19 infection who tested positive using a nasopharyngeal swab
  • Earliest detection: Day 1 of symptoms
  • Peak levels highest within week 1 and therefore probability of detection will be highest during that time
  • Viral load declines by week 3 and therefore virus more likely to be undetectable in to week 4
  • Infection severity: More virus may be present in patients with severe disease and therefore it may take longer to obtain a negative test result vs someone with a mild COVID-19 infection

Performance of RT-PCR Viral Tests

• RT-PCR specificities are close to 100% because they target specific RNA sequences of the SARS-CoV-2 virus
• False negative results may be due to
  • Inappropriate timing of collection vs symptom onset
  • Poor sampling technique (need to sample at the back of the nose)
• False positive results may occur due to lab error or contamination
• However, even with good analytic performance, PPV and NPV are related to prevalence and therefore can differ between geographic regions
  • In a setting with high COVID-19 prevalence, a negative test does not necessarily rule out the possibility that an individual is infected with SARS-CoV-2

Antibody Testing

General CDC Antibody Guidance

• According to the CDC

Antibody testing does not replace virologic testing and should not be used to establish the presence or absence of acute SARS-CoV-2 infection

Antibody testing is not currently recommended to assess for immunity to SARS-CoV-2 following COVID-19 vaccination, to assess the need for vaccination in an unvaccinated person, or to determine the need to quarantine after a close contact with someone who has COVID-19

Some antibody tests will not detect the antibodies generated by COVID-19 vaccines

Because these vaccines induce antibodies to specific viral protein targets, post-vaccination antibody test results will be negative in persons without history of previous infection, if the test used does not detect antibodies induced by the vaccine

• In general, antibodies will be detectable 7 to 14 days after illness onset and will be present in most people by 3 weeks
  • Infectiousness likely decreased by that time
  • Evidence suggests some degree of immunity will have developed
• IgM and IgG can appear together, usually within 1 to 3 weeks
  • IgG antibodies appear to persist for at least several months
  • Some individuals may be infected but will not develop antibodies
• Neutralizing antibodies can also be identified and are associated with immunity
• FDA requires companies providing antibody testing to obtain an EUA

What Are the Different Types of Antibody Tests?

• Antigenic Targets
  • Spike glycoprotein (S): Present on viral surface and facilitates virus entry
  • Nucleocapsid phosphoprotein (N): Immunodominant and interacts with RNA
  • Protein targeting is important to reduce cross-reactivity (cause of false positives which may occur with other coronaviruses like the common cold) and improve specificity
• Types of Antibody Testing
  • Binding antibody detection that use purified SARS-CoV-2 (not live virus)
    • Point-of-care (POC) tests
    • Laboratory tests that usually require skilled personnel and specialized equipment
  • Neutralizing antibody detection (none currently FDA authorized)
    • Serum or plasma is incubated with live virus followed by infection and incubation of cells
    • Can take up to 5 days to complete the study

When Can Antibody Testing be Helpful?

Antibody testing may be helpful in the following situations

• Seroconversion: In a patient who did not receive a positive viral test
  • A positive antibody test at least 7 days following acute illness onset but a previous negative antibody test may indicate new onset SARS-CoV-2 infection
• To support a diagnosis in the presence of a complex clinical situation, such as patients who present with COVID-19 complications (e.g., multisystem inflammatory syndrome and other post-acute sequelae of COVID-19)
  • Note: Due to antibody persistence, a single positive antibody test result may reflect previous SARS-CoV-2 infection and not a recent illness
• Clinical, occupational health, and public health purposes, such as serologic surveys

Vaccination and Test Interpretation

• In a person never vaccinated
  • testing positive for antibody against either N, S, or RBD indicates prior natural infection
• In a vaccinated person
  • Testing positive for antibody against the vaccine antigen target, such as the S protein, and negative for other antigen: Suggests vaccine-induced antibody and not SARS-CoV-2 infection
  • Testing positive for any antibody other than the vaccine-induced antibody, such as the N protein: Indicates resolving or resolved SARS-CoV-2 infection that could have occurred before or after vaccination
• The CDC states that

SARS-CoV-2 antibodies, particularly IgG antibodies, might persist for months and possibly years

Therefore, when antibody tests are used to support diagnosis of recent COVID-19, a single positive antibody test result could reflect previous SARS-CoV-2 infection or vaccination rather than the most recent illness

Learn More – Primary Sources:

CDC: Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons for Coronavirus Disease 2019 (COVID-19)

Interim Guidelines for COVID-19 Antibody Testing in Clinical and Public Health Settings

CDC: Overview of Testing for SARS-CoV-2

Interpreting SARS-CoV-2 Test Results

The Promise and Peril of Antibody Testing for COVID-19

EUA Authorized Serology Test Performance

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