28 March 2022 Episode 252: True COVID death toll;  T cell responses and reinfection risk; children; fourth dose; co-infections

Dear colleagues,

I guess we all get reminded daily that the pandemic is not really over, as we learn that family members, colleagues and friends have to isolate themselves with Omicron BA.2.   Not only the numbers of infections, but also hospitalization and deaths are rising again.

The COVID literature is still flourishing too, with nice papers and reviews on various topics, some of which I’d like to share with you.

Par 1 on true death toll in the world;

Par 2 on long-term immunity and protection after primary infection

Par 3 on omicron and children

Par 4 on the experience with fourth dose in Israel

Par 5 on effect of SARS-CoV-2 on other viral infections

Par 1 What is the true COVID toll in Africa and in the world?

Ep 252-1: the case of Zambia Gill et al medRxiv 22 March 2022.  According to a systematic postmortem study in Lusaka over 2 years, 32 % of all deaths could be attributed ton COVID-19 and the percentage was substantial across all age groups, including children below 5 and young adults, suggesting a different pattern compared to high income countries.

Taking into account the next study on excess mortality, the official death toll from COVID-19 in Zambia of 4,000 people could be 20 times underestimated (rather 80,000!)

Ep 242-2: Study by  Haidong Wang  in Lancet 10 March, the global excess mortality due to COVID over 2020-21 is 18 million, rather than 6 million according to official WHO statistics (https://www.who.int/data) . 

Excess deaths due to COVID-19 were estimated in India 4·07 million, the USA 1·13 million, Russia 1·07 million, Mexico 798 000, Brazil 792 000, Indonesia 736 000 and Pakistan 664 000.

Some differences between reported and estimated mortality from the table: 

CONCLUSION par 1:

Very substantial underestimation of death toll by COVID-19, especially in large parts of Africa, Asia, Eastern Europe and Latin-America  

Par 2 Long-term effects of infection on immunity and reinfection

Stability and breath of T cell responses after infection

Ep 252-3:  Li Guo Lancet Microb Infect 23 March 2022 present a very comprehensive study on humoral and cellular responses in recovered subjects up to 12 months after infection with Wuhan strain:

1. Neut Ab similar according to disease severity and age, slightly waning over 12 months
2. T cell responses against all components, also similar according to disease severity
3. While neut Ab against other variants clearly lower, T cell responses unaffecte

Conclusion:

• Robust antibody and T-cell immunity against SARS-CoV-2 is present in the majority of recovered patients 12 months after moderate-to-critical infection.
• Total SARS-CoV-2-specific T-cell responses remain effective against variants, but neutralizing antibodies diminish by 12 months and are less effective against variants (omicron not yet considered).

Ep 252-4: Michlmayr SSRN Lancet 10 March 2022 systematic review on reinfection risk

Before omicron: protection against re-infection higher than 80 %, only 1 % of all cases, and stable for 10 months

Omicron: drop of protection to 19 %; risk 5.5 X higher

Nevertheless, older subjects (> 65 yrs) less protected: only 35 % (yp to June 2021 = Ancestral- Alpha Delta)

Over a third of subjects with first ASY infection, experience symptoms at re-infection

Note: the term “natural immunity” is used more and more as a synonym of infection-induced immunity.  I do not agree for two reasons:

• It is confusing, since “natural immunity” is also used as a synonym of “innate immunity”, which is based on interferon, NK cells etc; while infection-induced immunity is  rather based on “adaptive immunity” (antibodies and T cells)
• In the lay press, “natural immunity” may sound more positive than it should be and could be opposed to the “un-natural immunity”, induced by vaccination, while we know that vaccines are much more safe than infection at all ages to induce immunity. 

However, I’m afraid we will not be able to change this unfortunate use of “natural immunity”.

Ep 252-5: Lentini medRxiv 27 March: Higher viral load of omicron BA-2 probably explains why it rapidly outcompetes BA-1

Based on RT-PCR assay to simultaneously and robustly call general COVID19 status and Omicron BA.1 variant status in a single RT-PCR reaction, which enabled real-time tracking

of the Omicron BA.1/BA.2 transition in Sweden.

• the predominant Omicron BA.1 variant was outcompeted by Omicron BA.2
• cases of BA.2 infection presented nearly two-fold higher quantities of viral RNA in nasopharyngeal sabs compared to BA.1 infection,

Suggesting that increased viral load in the upper pharynx may contribute to BA.2 being more

contagious than the BA.1 lineage.

CONCLUSION par 2

Sustained and broad T cell responses after infection, along with neut Ab,  possible explanation for robust protection against re-infection

Omicron BA-1 and BA-2 clearly “break through” this infection induced protection, with BA-2 even more contagious than BA-1

Par 3  COVID in children and youngsters

Ep 252-6: Winnie Tso in SSRN Lancet 21 March with a systematic review on Omicron severity. 

Omicron BA.2 in children who had no past COVID-19 or vaccination 

• higher odds of PICU admissions, mechanical ventilation and oxygen use.
• more neuropathogenic than previous SARS-CoV-2 variants, influenza and parainfluenza viruses, resulting in more seizures.
• targets the upper airways more than past variants and influenza, with “croup” like symptoms

Ep 252-7: Powell Lancet Infect Dis 21 March Effectiveness of Pfizer against symptomatic PCR+ COVID in (A) 12-15 years and (B) 16-17 years in UK.  

Effectiveness after 2nd dose = high after 2 weeks, also against omicron, but  wanes quickly in 16-17 years (see B).

In adults from the UK, a similar vaccine effectiveness against symptomatic disease was observed for both the delta (91%) and omicron (66%) variants 2–4 weeks after two BNT162b2 doses given 8–12 weeks apart, which was similar to data from South Africa reporting vaccine effectiveness of 70% against the omicron variant 2 weeks or more after the second vaccine dose.

The rapid waning of protection after the first and second BNT162b2 dose against symptomatic disease with the omicron variant implies that current adolescent immunisation programme unlikely to sustain suppression of infections in the medium-to-long term. If the aim of the programme is to reduce infections, then regular boosters will likely be needed

Ep 252-8: Nafylian Office for National Statistics England March 2022

• No evidence of a change in the number of cardiac-related deaths or death occurring from any cause after COVID-19 vaccination in people aged 12 to 29 years in England.
• More deaths were registered in young people aged 15 to 29 years in England in 2021 than the average in 2015 to 2019; however, no excess for deaths from circulatory diseases.
• Deaths in 2020 increased for some causes, particularly suicides in young females and drug poisonings in young males.

Ep 252-9: The Guardian reports on recent worrying rising absence of children in English schools, as a consequence of (too much?) relaxation of measures.

The government urgently needs to remind people that just because the legal requirement to isolate has been removed, there is still a duty to take appropriate action to reduce the spread of Covid – just like any other illness.

Covid hasn’t gone away and we need a proper plan for how to live with it long term that is focused on keeping levels low and reducing disruption.

CONCLUSIONS Par 3

• Unvaccinated children, infected with omicron, have a significant risk on hospitalization and severe disease
• Confirmation that vaccine efficiency in children is similar to adults, including waning.  No signal of increased cardiac  mortality (as a consequence of myocarditis)
• Worrying trend of absence in school in England

Par 4 Usefulness of fourth Pfizer dose

Ep 252-10 = Ep 250-0:  Regev-Yochay NEJM 16 March 2022: Limited effect of fourth RNA dose in HCW in Israel

• Maximal immunogenicity of mRNA vaccines is achieved after three doses and that antibody levels can be restored by a fourth dose.
• Low vaccine efficacy of fourth dose against infections in health care workers, as well as relatively high viral loads suggesting that those who were infected were infectious.

Thus, a fourth vaccination of healthy young health care workers may have only marginal benefits. Older and vulnerable populations were not assessed.

Ep 252-11:  Bar-On medRxiv 1 Feb performed a population study in January 2022 in over a million 60+ Israelis who had received a 4th dose versus those who had only received 3 doses:

• reduction of infection by a factor 2
• reduction of severe illness by a factor 4

But the follow-up was limited to 23 days after 4th dose.

Ep 252-8: Ronen Arbel SSRN Lancet in a similar (partly overlapping) Israeli population, mortality was reduced by a factor 4.5 (HR = 0.22).  Clearly, a lot pf comorbidities were present (see Table 2).

Clearly, this study is in line with the previous one, but it also limited to 40 days

Ep 250-12: Sivan-Gazit medRxiv 24 March 2022 a smaller Israeli study in a similar population (> 60 yrs), but followed up over  70 days.  As can be seen, after 40 days, the effectiveness against infection declines, but remains high against severe disease.  

CONCLUSION: according to these Israeli data, a fourth dose seems useful in the elderly. 

With regard to other indications: 4th dose has been administered in many countries to people with an immune compromising condition, including congenital immune disorders, people who receive chronic kidney dialysis, certain HIV patients, people with blood cancer or other malignant tumors or patients who have undergone a stem cell or organ transplant.  There are several reports on increased antibody responses, but to my knowledge, no large scale studies on effectiveness.

Ep 252-13: Brussels Times 17 March states that the Belgian Vaccination Task Force estimates that there is too little scientific evidence to justify a fourth shot for the general population.

Nevertheless France started offering a fourth dose to over 80swho had their booster more than three months ago on Monday and the UK is expected to start offering everyone over 75 years old a second booster dose from April.

Par 5 Negative and positive news on viral co-infections

Ep 252-14: Swerts Lancet 25 March: Influenza (and Adeno’s) are killers in COVID patients

Investigation for viral co-infection in almost 7000 COVID subjects:  

• 227 had influenza viruses,
• 220 respiratory syncytial virus,
• 136 adenoviruses. 

Ep 252-15: Chen found a strong association between COVID-19-related disruption (as measured independently by public health and social measures and human movement behaviours) and reduced dengue risk, even after taking into account other drivers of dengue cycles including climatic and host immunity (relative risk 0·01–0·17, p<0·01).

Overall, we estimate that 0·72 million (95% CI 0·12–1·47) fewer dengue cases occurred in 2020 potentially attributable to COVID-19-related disruption.

I hope you enjoyed reading

Best wishes,

Guido