10 Jan 2022 Episode 220 Why we should have vaccinated our (grand)children the day before yesterday

Episode 220: Why we should have vaccinated our (grand) children the day before yesterday.

Dear colleagues,

I admit this is a “provocative” (or at least not neutral) title and in fact, I’m writing this episode, because I feel a lot of questions and hesitation around me.  Only today, I received two mails with questions on the topic.  As you know, I presented a lot of evidence over the last two weeks, but in a scattered fashion.  In this episode, I just bring it all together again and try to make my conclusions.  

The only “new” paper (dating from 21 Dec), presenting the data from Tshwane, showing that for some kids, especially the youngest and most vulnerable ones, omicron is NOT a trivial infection (see below Ep 220-1).

All the papers from the various episodes are collected again on our website under Episode 220 for your convenience.    

Here is my “synoptic” summary:

1. Children are (almost?) equally susceptible to SARS-CoV-2 infection than adults and they readily transmit the virus amongst each other and to adults in households and schools.
2. Happily, children are mostly a- or pauci-symptomatic.  The main reason is their well-functioning innate immunity and in particular the type 1 interferon system (see Ep 191-11 and -12).  In addition, there is also evidence for more robust adaptive SARS-CoV-2 specific T cell and neutralizing antibody responses (See 211-6). Moreover, there is some controversial literature on cross-protection from common Coronaviruses (See Ep 191).    
3. Nevertheless, all SARS-CoV-2 variants,  including omicron, can affect children badly.  While children with underlying morbidities have a much higher chance of being hospitalized and die, the still somewhat enigmatic MISC syndrome is mostly seen in children, who were previously perfectly fit. Hence complicated COVID is rare, but it happens, it is serious and it is not predictable.  See 211-1; 217-1 and -2
4. The risk on post-acute COVID is another matter of concern, but the size and seriousness of this phenomenon in small children are less clear and merit more longitudinal and in depth investigations.
5. Trials with Pfizer mRNA vaccine in adolescents (12-17) and younger children (5-11) have shown protection against infection (admittedly in the pre-omicron period); and, more importantly  a very strong protection against MISC (admittedly only shown in adolescents and in the pre-omicron period). See Ep 219-1 and -2
6. The large study published on 31 Dec in MMWR on over 8 million 5-11 years old US children shows that Pfizer vaccine does have local and systemic side effects, including very rare cases of myocarditis, as could be expected from experience in older age groups, but no very serious, let alone deadly complications. Thus  weighing these mostly somewhat “annoying” side effects against the small, but real risks of serious COVID clearly shows a positive risk/benefit. See 213-6.
7. The Danish household study confirms that omicron is much more infectious than delta, but also indicates that full vaccination (+ booster) had a significant effect against omicron transmission.  Although not focused on children (who presumably were not yet vaccinated at the time), it is very likely that their vaccination would help to mitigate unchecked omicron spread in households and schools (Ep 212-6)

Much more can be said and nuances could be made. Therefore, your comments and suggestions are always welcome.     

Ep 220-1: Pediatric omicron cases in Tshwane District (metropolitan area of 7000 km2 with over 3 million inhabitants in Northern Gauteng, South-Africa) in Nov-Dec 2021

Out of almost 6,400 pediatric cases, 7 % (462) were hospitalized and on 139 of those clinical information was available:

• In 44 % COVID was the primary diagnosis.
• Young children (0-4 yrs) were most affected.
• Symptoms included: fever> cough > vomiting > dyspnea, diarrhea  and convulsions.
• 25 % received oxygen, 6 % ventilated.
• 4 (3 %) children died, all with complex  co-pathologies.

Ep 191-11:  Carl Pierce et al in JCI Insight Feb 2021 provide direct evidence of more vigorous anti-viral and inflammatory response at the nasopharyngeal mucosa in children versus adults: besides confirming higher IL17-A and IFN-gamma (just like in blood see Ep 191-6) they now show also higher type 1 IFN and higher IL1beta and IL-18 at the mucosal site. 

Remarkable, levels of IgG and IgA antibodies were similar in children and adults.

 Ep 191-12:  A very elegant paper by Loske in Nature Biotechnology showing that the nasal mucosa in children is “pre-activated” for antiviral responses, because of higher basal expression of “RNA sensors” such as MDA5 and RIG-I in epithelial cells, macrophages and dendritic cells  (amongst other differences, such as presence of specialized CD8 T cells).

This is a groundbreaking paper, because it goes beyond associations and strongly suggests that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.

Ep 211-1: Miller describes in CID the evolution of Multisystem Inflammatory Syndrome in Children (MIS-C) linked to the first 3 COVID waves in the US (till July 2021).  Overall almost 4500 children were diagnosed with MISC of whom 37 died.  They show that  cardiovascular complications and clinical outcomes including length of hospitalization, receipt of ECMO, and death decreased over time, but you can appreciate in the figure that it remains a very serious condition

Ep 211-2: Michael Levy in JAMA provides the very good news that in French adolescents MISC did NOT occur in fully vaccinated subjects: out of 33 cases in Sept-Oct 2021 O was fully vaccinated, 7 had received 1 dose and 26 were unvaccinated. 

Ep 211-3: A case report of a 13 years old girl with sickle cell anemia, who presented with MISC, 2 months after full Pfizer vaccination.  She had a positive serology for nucleocapsid as evidence of (past) SARS-CoV-2 infection. She recovered after treatment with intravenous immunoglobulins and steroids.

Ep 211-4:  Another case report of a 12 years old boy, who presented with MISC symptoms 5 weeks after his second mRNA vaccine (first Pfizer, then Moderna).  He also recovered under a similar treatment, but antibodies to nucleocapsid were not measured. 

Ep 211-5: Patone medRxiv 25 Dec analyzes the myocarditis risk in England:

• Risk is lower after Adeno Astra-Zeneca as compared to Pfizer and highest for Moderna
• In people (men or women) over 40, the risk after SARS-CoV-2 infection is much higher (about 10 X) than after vaccination.
• In men under 40, the risk after infection is about 7 per million and after Pfizer in men, it is similar, but after the second Moderna dose, it is 101 per million.
• In women, the risk after infection and vaccination is similar.
• A third mRNA dose has only a risk of 2 per million (in over 40)

Ep 211-6: Dowell in Nature Immunology shows that after SARS-CoV-2 infection children have high common beta CoV (HKU-1 and OC43), but not alpha. Neutralization is robust and declines much slower than in adults.

Spike-specific T cell responses were more than twice as high in children and were also detected in many seronegative children, indicating pre-existing cross-reactive responses to seasonal CoV.  

We previously showed that the first line of defense against SARS-CoV-2, the interferon system, functions much better in children. 

Summary:

• MISC, the most serious complication in children, seems preventable with mRNA vaccination, with only 2 reported exceptions.
• Pfizer may be a better choice than Moderna in children, in view of myocarditis risk
• As expected, antibody and T cell responses after SARS-CoV-2 in children are more robust and sustained, but I could not find data on duration of antibody response after vaccination in children. 

Ep 212-6: Evidence of higher transmissibility of omicron compared to delta in Danish households:

• Secondary attack rate = 31 % for omicron and 21 % for delta.
• Omicron infected unvaccinated 1.17 x more than delta, but 2.6 X more in 2 dose vaccinated and 3.6 X more in 3 dose vaccinated!  Hence very clear immune escape   (See Table 1)

The good news: full vaccination protects against delta, but not omicron, while booster protects clearly against both delta and omicron (Table 2).

Ep 213-3: Ward in Nature Medicine 20 Dec 2021 provides an overview of all pediatric admissions to a pediatric intensive care unit (PICU) and of MISC or PIMS-TS (pediatric inflammatory multi-system syndrome temporally associated with SARS-CoV-2) during the first year of the pandemic in England.

Out of 12 million youngsters (0-17 yrs):

Overall:

• Hospital admissions for COVID:  5830
• Transfer to PICU = 251
• Deaths = 8

PIMS-TS:

• Diagnoses: 690 (most in hospital)
• PICU: 309
• Deaths < 5
• Tended to be older and non-White
• Remarkably: most MISC-PIMS were previously healthy: ¾ no previous admission to hospital!

PICU admissions (= 251)

• More in babies < 1 year and especially < 1 month
• More in boys
• 91 % had underlying co-morbidity (cancer/hematological disease, cardiovascular, respiratory, neurological)

Ep 213-4: Reinfection rate in children Jan 2020-July 2021 in UK (Mensah medRxiv 11 Dec 2021-

Children had a lower risk of reinfection than adults 0.34 vs 0.73 %),

• were not associated with more severe disease or fatal outcomes.
• strongly related to exposure due to community infection rates,
• especially during the Delta variant wave.

Situation may change with omicron!?

Ep 213-6: Hause MMWR 31 Dec 2021 on side effects of 8.2 million Pfizer in 5-11 years old children

1. 4,249 passive reporting via Vaccine Adverse Events Reporting System (VAERS) of which
   • 97.6 % “not serious” mostly related to dosing or product preparation
   • 100  cases more serious
     • 29 fever
     • 21 vomiting
     • 15 increased troponin
     • 12 seizures
     • 11 myocarditis (all recovering)
     • 2 girls died of a complicated underlying disease (not related, but still under review)
2.  42,504 children in a more active “v-safe” program uncovered more side effects:
   1. 55 % local and 35 % systemic
   2. Most common: injec­tion site pain, fatigue, and headache.
   3. Fever: more after dose 2 (13%) than dose 1 (8%).
   4. Child unable to perform normal activity the day after dose 1 (5%) and dose (7%).
   5. 1 % was seeking medical care and of those 14 (0.02%) went to hospital: appendicitis (two), vomiting and dehydration (one), respiratory infection (one), and retropharyngeal cellulitis (one).

All in all, very reassuring data, but parents … should be advised that local and systemic reactions are expected after vaccination … and are more common after the second dose.   

Ep 216-4: Vaccination of children

1. An  interview with Dr Hills (Columbia), pleading for vaccination in children, because in New York they see a huge surge of hospitalization of unvaccinated children (contributed by P Smits). 

                https://www.youtube.com/watch?app=desktop&v=jXymNkUDJFY

2. Point of view of Dr. Plotkin (contributed by P Vandamme)

My view is that children should receive vaccination because

1. There is a considerable amount of disease in them, particularly recently.
2. They will grow up and socialize.
3. We need as much immune population as possible.
4. The omicron variant will ultimately infect them anyway, and they are better off undergoing infection when vaccinated.
5. Actually, I don’t think this is always true that infection protects better than vaccination, judging from the numbers of reinfections.  COVID is a mucosal infection, not viremic, so reinfection can take place unless the individual has a broad immune response.  Mucosal infections often do not leave permanent immunity, and a single dose of vaccine is recommended post-infection to assure a high immune response.  Also, the more virus excreted by children the more exposure to their parents and grandparents.  Letting children act as disseminators would work only if infection in older people is harmless.

By the way, I am switching my attention from variant-specific vaccines to vaccines that might protect against all betacoronaviruses, for which there have been promising publications on how to do that from several laboratories.  We can’t keep on chasing mutations.

CDC Recommends Pediatric COVID-19 Vaccine for Children 5 to 11 Years

Media Statement

For Immediate Release: Tuesday, November 2, 2021
Contact: Media Relations
(404) 639-3286

Today, CDC Director Rochelle P. Walensky, M.D., M.P.H., endorsed the CDC Advisory Committee on Immunization Practices’ (ACIP) recommendation that children 5 to 11 years old be vaccinated against COVID-19 with the Pfizer-BioNTech pediatric vaccine. CDC now expands vaccine recommendations to about 28 million children in the United States in this age group and allows providers to begin vaccinating them as soon as possible. 

COVID-19 cases in children can result in hospitalizations, deaths, MIS-C (inflammatory syndromes) and long-term complications, such as “long COVID,” in which symptoms can linger for months. The spread of the Delta variant resulted in a surge of COVID-19 cases in children throughout the summer. During a 6-week period in late June to mid-August, COVID-19 hospitalizations among children and adolescents increased fivefold. Vaccination, along with other preventative measures, can protect children from COVID-19 using the safe and effective vaccines already recommended for use in adolescents and adults in the United States. Similar to what was seen in adult vaccine trials, vaccination was nearly 91 percent effective in preventing COVID-19 among children aged 5-11 years. In clinical trials, vaccine side effects were mild, self-limiting, and similar to those seen in adults and with other vaccines recommended for children. The most common side effect was a sore arm. 

COVID-19 vaccines have undergone – and will continue to undergo – the most intensive safety monitoring in U.S. history. Vaccinating children will help protect them from getting COVID-19 and therefore reducing their risk of severe disease, hospitalizations, or developing long-term COVID-19 complications. Getting your children vaccinated can help protect them against COVID-19, as well as reduce disruptions to in-person learning and activities by helping curb community transmission. 

Distribution of pediatric vaccinations across the country started this week, with plans to scale up to full capacity starting the week of November 8th. Vaccines will be available at thousands of pediatric healthcare provider offices, pharmacies, Federally Qualified Health Centers, and more.   

The following is attributable to Dr. Walensky:

“Together, with science leading the charge, we have taken another important step forward in our nation’s fight against the virus that causes COVID-19. We know millions of parents are eager to get their children vaccinated and with this decision, we now have recommended that about 28 million children receive a COVID-19 vaccine. As a mom, I encourage parents with questions to talk to their pediatrician, school nurse or local pharmacist to learn more about the vaccine and the importance of getting their children vaccinated.” 

And finally a number of papers that plead for vaccination vs infection

https://directorsblog.nih.gov/2021/06/22/how-immunity-generated-from-covid-19-vaccines-differs-from-an-infection/amp/

https://covid.joinzoe.com/post/covid-vaccine-natural-immunity-difference#part_3

https://publichealth.jhu.edu/2021/why-covid-19-vaccines-offer-better-protection-than-infection

https://www.henryford.com/blog/2021/10/natural-antibody-protection-vs-vaccine-protection

https://www.hopkinsmedicine.org/health/conditions-and-diseases/coronavirus/covid-natural-immunity-what-you-need-to-know?amp=true

https://www.nebraskamed.com/COVID/covid-19-studies-natural-immunity-versus-vaccination

Children in US and UK (pre-omicron)

Ep 217-1: Retrospective US study April 2020-Sept 2021 in 0-11 years old:

4,573 hospital admissions, 2/3 in 0-4 years and ¼ with immune compromise; 23 % in ICU and 7 % mechanical ventilation

… children aged 0-11 years can experience severe COVID-19 illness requiring hospitalization and substantial hospital resource use, further supporting recommendations for COVID-19 vaccination.

Ep 217-2: Birth cohort since 1997 of 1.226 million CYP in Scotland Feb-Dec 2020

• 179/1000 positive PCR and 29/1000 hospital admissions.
• As expected chronic conditions, particularly multiple types of conditions, was strongly associated with COVID-19-related admissions across all ages. (HR = 12)
• Nevertheless: 89 % of admitted children had no chronic condition recorded.

These results provide evidence to support risk/benefit analyses for pediatric COVID-19 vaccination programs

Ep 218-1: Still, more children are being hospitalised in the UK

Ep 218-2:  Similar, rather concerning data from New York on rapid increase of pediatric hospitalizations

Note on p 19 calculated VE against omicron-related hospitalization between 76 and 95 % in children !

Protection of adolescents against Multisystem Inflammatory Syndrome in Children (MISC)

Ep 219-1: Clear protection in French adolescents: Of  33 hospitalizations Sept-Oct 2021 (Delta VOC), none had been fully vaccinated with Pfizer, 7 had received 1 dose and 26 were unvaccinated.  

Ep 219-2:  The US study is larger done between July–December 2021, a period of Delta variant.  Amongst 102 MIS-C case-patients, five (5%) were fully vaccinated with 2 doses ≥28 days before hospitalization, and 97 (95%) were unvaccinated. Vaccine efficacy was 91 %.   No fully vaccinated patients with MIS-C required respiratory or cardiovascular life support, as opposed to 39% of unvaccinated MIS-C patients. 

Best wishes,

Guido