Archives for February 2021

Asif Noor, MD, FAAP

Theresa Fiorito, MD, FAAP

Dr. Asif Noor, MD, FAAP is a Pediatric Infectious Disease Specialist at NYU Winthrop Hospital and he co-chairs the Infectious Disease Committee of the NYS AAP Chapter 2)

Dr. Theresa Fiorito, MD, FAAP is a member of the Infectious Disease Society of America, Society for Pediatric Research, Pediatric Infectious Diseases Society, American Academy of Pediatrics, and the International Society of Travel Medicine with a Certificate in Travel Health.

An entire year has elapsed since the first confirmed case of COVID-19 infection in New York. Pediatricians were in the forefront of an uphill battle during the spring outbreak and continue battling COVID-19 during the winter months.

Although children were largely spared, pediatricians encountered multiple challenges to which they responded methodically.  Whether it was protecting a newborn from maternal COVID-19, providing care to sick children in the office setting, dealing with mental health issues associated with the pandemic, or managing a novel condition in children, multisystem inflammatory syndrome in children (MIS-C), pediatricians promptly adapted.

On December 11, 2020, the FDA granted emergency use authorization (EUA) for the first COVID-19 vaccine by Pfizer/BioNTech.  As of February 6^th, 2021, 59 million doses have been manufactured and 39 million have been administered in the U.S. Currently, the COVID-19 vaccine is being offered to the high-risk groups identified by the Advisory Committee on Immunization Practices (ACIP) based on the ethical principles of initial allocation. This includes pediatricians.  Many of us are thankful to receive it immediately after the EUA, particularly if we were associated with a hospital or medical center.  However, many of us working in an office witnessed firsthand the uncoordinated vaccine distribution with no clear guidance.

Children under 18 years comprise a quarter of the U.S. population and their immunization is vital to attain a goal of herd immunity.  Pediatricians are commonly questioned on the availability of COVID-19 vaccine in children.  The pediatric population needs to be immunized to not only protect them directly, but also to indirectly insulate the most vulnerable populations.

We, the pediatricians, serve as the primary advocate to deliver a clear and compassionate message on vaccine safety and efficacy.  Conducting COVID-19 vaccine trials in children is imperative alongside the vaccine rollout to the elderly and most vulnerable populations.

In this blog, we will review the basics of COVID-19 vaccines, vaccine eligibility, vaccination in pregnancy& lactating persons, vaccination in children, and an update on MIS-C.

COVID Vaccine: Pipeline

As of February 6, 2020, there are 67 vaccine candidates in human trials, with 4 vaccines fully approved for use worldwide. In the United States, the mRNA vaccines from Pfizer/BioNtech and Moderna are currently being utilized.

Vaccine target: The major antigenic target for COVID-19 is the large surface spike protein.  This antigen allows the virus to bind to angiotensin-converting enzyme 2 (ACE-2) on the host cell and induce membrane transfusion.  A vaccine that can induce antibodies against the receptor binding protein of spike protein can prevent attachment to the host cell and neutralize the virus.

Vaccine platforms:COVID-19 vaccines are being developed using different platforms. As pediatricians, we are familiar with the traditional approaches applied to inactivated vaccine (e.g. inactivated influenza) and live vaccine (e.g. measles) technology.  The genetic sequence of COVID-19 published on January 11, 2020, led to a rapid emergence of new vaccine research and collaboration. It paved the path for the first two vaccine candidates currently authorized for use in the United States, using an mRNA platform.  Other vaccine candidates use replication–incompetent vector vaccines, recombinant protein vaccines, etc.

mRNA technology: The mRNA is delivered in lipid vesicles. After administration, the mRNA is translated into the target protein which is intended to elicit an immune response.  The mRNA does not enter the nucleus or interact with host DNA.  The normal cellular processes degrade it quickly.

Immunogenicity and efficacy: Phase 2 (small scale immunogenicity, safety and efficacy trials) and phase 3 trials (large-scale safety and efficacy trials) have demonstrated the production of neutralizing antibody responses comparable to those in convalescent plasma from patients with asymptomatic to moderate COVID-19 infection.  Clinical trials have demonstrated vaccine efficacy of 95 and 94.1% in the Pfizer/BioNTech and Moderna studies, respectively, in preventing symptomatic COVID-19 infection after receipt of 2 doses.

Reactogencity (reactions that occur soon after vaccination; a physical manifestation of response): There are no serious safety concerns.  All vaccines elicit systemic adverse effects or reactogenicity such as fevers, chills, headaches, fatigue, and/or myalgias in a small portion of participants.  Most adverse effects are mild to moderate, and occur in the first 3 days after receiving the vaccine.  Symptoms are more frequent after the second dose, and in younger persons compared to older recipients.  Antipyretics or analgesics may be taken for post-vaccination local or systemic symptoms, however, routine prophylactic administration is not currently recommended.

Anaphylaxis following vaccination has been reported in an approximate rate of 5 events per 1 million doses. Out of these cases, 80% occurred in persons with a history of anaphylaxis, and 90% occurred within 30 minutes of vaccine receipt.

Vaccine effectiveness against variants: In the Pfizer/BioNTech cohort, the plasma from vaccinated clinical trial participants appeared to maintain neutralizing activity against the B.1.1.7, or the U.K. variant strain.  It also neutralized virus containing the key mutations in the B.1.351, or the South African variant, however the neutralizing titers were lower with South African strain.   Similar results have been found in Moderna’s in vitro neutralization studies.

COVID vaccine: Pregnant and lactating women

There are currently no safety data available on COVID-19 vaccines in pregnant persons. Data extrapolated from animal studies did not demonstrate any safety concerns in pregnant rats receiving the Moderna vaccine. Studies in pregnant animal models receiving the Pfizer/BioNTech vaccine are ongoing; it is of note that during the Pfizer/BioNTech clinical trials in humans, 23 persons became pregnant after receiving the vaccine, and to date, no adverse effects in these patients have been reported.

While absolute risk is low, pregnant women are at increased risk of severe illness from COVID-19 infection.  They may also be at increased risk of pregnancy complications, such as preterm labor. As per the ACOG (American College of Obstetricians and Gynecologists), COVID-19 vaccines should not be withheld from pregnant or lactating individuals if they are part of a group recommended to receive the vaccine (e.g., health care personnel, essential workers).  The Centers for Disease Control and Prevention (CDC) and ACIP also recommend that pregnant or lactating persons within eligible populations be offered the COVID-19 vaccine.  The Society for Maternal Fetal Medicine (SFM) advocates for all pregnant persons to have access to COVID-19 vaccines.

These organizations emphasize the importance of shared clinical-decision making; the decision for pregnant persons to get vaccinated should be based on an individual’s unique risk for infection.  For example, someone who is able to work from home through the entirety of the pregnancy has a low exposure risk, and may want to wait to get vaccinated until after the birth of the child.

Those trying to become pregnant do not need to avoid pregnancy after receipt of COVID-19 vaccination, nor is there any evidence that COVID-19 vaccination has any effect on fertility.

COVID vaccine: Children

Currently, the Pfizer-BioNtech mRNA vaccine is approved for ages 16 and up, and the Moderna mRNAvaccine is approved for ages 18 and up.

There is currently no COVID-19 vaccine available for children under age 16. However, studies in pediatric populations are ongoing.  Moderna is currently enrolling patients for a phase 2/3 randomized study to evaluate the safety, effectiveness, and reactogenicity in those 12-18 years of age. Pfizer is conducting a similar study in those 12-15 years of age.   Results of clinical trials on children under age 12 for both vaccines will likely take much longer, as dosing adjustments for age will need to be made.  AstraZeneca, whose COVID-19 vaccine is not yet approved in the United States (but is approved for use in the U.K.), also plans to commence clinical trials for those ages 5-18 years.  It is of note that obtaining study patients under age 12 is currently proving difficult; parents are finding it hard to justify enrolling their children in these trials.  While there is clearer evidence of spread of COVID-19 among teenaged children, transmission has been reported in those as young as age 8.  Given the accelerated nature of vaccine development, there is a preponderance of misinformation circulating, particularly online, regarding vaccine safety, which can contribute to skepticism and vaccine hesitancy.  As a pediatrician, we can identify concerns, educate patients on vaccine risks and benefits, and dispel the myths.  The most effective intervention against vaccine hesitancy is communication by a primary care provider.

Winter outbreak and multisystem inflammatory syndrome in children (MIS-C):  The initial emergence of MIS-C in New York was observed in May and June of 2020.  This preceded the peak of the COVID-19 epidemic in New York by 1-2 months.  In winter, a similar trend of MIS-C cases is being observed in January and February of 2021.

Much has been learned about the wide spectrum of clinical presentations and management of MIS-C.  Presentation ranges from a shock–like picture, to a Kawasaki disease-like presentation, to milder forms with brief febrile illnesses.  The median age of patients is 9 years.  All of them have fever, 88% have gastrointestinal (GI) symptoms, 60% have a rash, and 50% have conjunctivitis.  Children with fever ≥ 4 days without any source, with either GI symptoms, rash, conjunctivitis, oral mucosal changes, extremity changes, neurological symptoms, or lymphadenitis should be evaluated for MIS-C.

Some interventions such as intravenous immunoglobulin (IVIG)and/or prophylactic antithrombotic therapy are appropriate for most children presenting with moderate to severe disease, regardless of the dominant type of presentation. Children presenting with Kawasaki-type disease should receive standard therapies for Kawasaki disease such as IVIG and aspirin.  Children with cardiac involvement may present with arrhythmia and hemodynamic compromise.  Although IVIG can be used in myocarditis, the conclusive evidence of benefit is lacking.  In addition, based on severity of illness, low-dose methylprednisolone (2 mg/kg/day twice daily) or pulse steroids (30 mg/kg/day for three days) should be considered in hospitalized children.

Over the next 1 to 2 months, pediatricians should stay vigilant in triaging febrile illnesses that may be consistent with MIS-C in the office setting.

References:

1. https://www.cdc.gov/mmwr/volumes/69/wr/mm6947e3.htm
2. https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html
3. https://www.cdc.gov/mmwr/volumes/69/wr/mm695152e2.htm?s_cid=mm695152e2_w
4. https://www.acog.org/covid-19/covid-19-vaccines-and-pregnancy-conversation-guide-for-clinicians
5. https://s3.amazonaws.com/cdn.smfm.org/media/2591/SMFM_Vaccine_Statement_12-1-20_(final).pdf
6. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/pregnancy.html
7. https://www.acog.org/clinical/clinical-guidance/practice-advisory/articles/2020/12/vaccinating-pregnant-and-lactating-patients-against-covid-19
8. https://www.clinicaltrials.gov/ct2/show/NCT04649151?term=pediatric&cond=covid-19+vaccine&draw=2&rank=3
9. https://www.clinicaltrials.gov/ct2/show/NCT04368728?term=pediatric&cond=covid-19+vaccine&draw=2&rank=4
10. https://www.nichd.nih.gov/sites/default/files/inline-files/NICHDCouncil_Erbelding_090720V2.pdf