2 feb 2022 Episode 234 : Omicron sublineages, protective effect of breakthrough infections and vaccines, fourth dose and vaccine for children under 5.

Dear colleagues,

In this episode I will give an update on:

1. Omicron sublineages
2. Is omicron (breakthrough) infection is as protective as delta?
3. How is booster vaccine effectiveness evolving?
4. Do we need a fourth dose?
5. Progress in vaccine approval for children under 5 and its US context   

As you will see, several of these topics are highly debated and as usual, time will bring more insight….

With many thanks to Patrick Smits for all the input.

Papers see:

1. Transition from BA.1 to BA.2

Ep 234-1: Plesner Lyngse (medRxiv 30 Jan ’22) in Danish households: BA.2 clearly more transmissible than BA.1 (secondary attack rate 39 % vs 29 %):

• Susceptibility is increased in all cases: Odds Ratio’s BA.2/BA.1= 2.19 (unvaccinated) 2.49 (2 X vaccinated) and 2.99 (booster vaccinated).
• Transmissibility only increased in unvaccinated OR = 2.69   

More information also in the Financial Times (for those who have access): https://www.ft.com/content/e375b377-6f1b-4bf8-b6f7-9dce20908e72

For all others (including myself), the headlines, as summarized by colleague Patrick Smits:

The BA.2 offshoot of the Omicron variant is more infectious and better at evading immune protection provided by vaccines than the original version,

The sub-variant, which was first detected in early December, already accounts for the vast majority of Covid-19 cases in Denmark and India . It is also spreading fast in South Africa, Germany and the UK.

Despite Denmark is pressing ahead with dropping most Covid restrictions on February 1, as the number of people admitted to hospital remained relatively low. 

But BA.2 “[does] not increase its transmissibility from vaccinated individuals with breakthrough infections”, researchers added.

Separate findings from the UK, found that while BA.2’s “growth advantage is currently substantial”, vaccines were equally effective against both versions of Omicron.

Mortenson said the virulence of the subtype was still unknown. However, he said the “limited” changes in Danish hospitalisations and deaths figures in recent weeks was “a source of comfort”. He said it suggested BA.2 was no more severe than BA.1.

Frederik Plesner Lyngse, a University of Copenhagen researcher and lead author of the study, said “one of the biggest questions” was whether BA.2 could rapidly reinfect people previously infected with the original version of Omicron.

Ep 234-2: Genomic surveillance in Belgium 1 Feb 2022

During the week of 24/1/2022, BA.1 and BA.1.1 jointly represented 90.1% (↘) of the strains, while BA.2 represented 5.8% (↗↗) and Delta  4% (↘↘). The share of BA.2 has doubled over one week. BA.2 will become dominant within the next month, possibly provoking a new rise of infections.

In fact, there are now 4 sublineages in omicron BA.1, BA.1.1, BA.2 and BA.3, of which BA.1.1 and BA.2 show a rising trend

As compared to BA.1: BA1.1. has only 1 mutation in S, thus probably no immune escape, but BA.2 has  12 mutations, thus potentially escaping from immunity induced by previous VOC and  BA.1

Severity of infections in KULeuven: Omicron is now dominant amongst severe cases, but number of severe and critical infections remain low and relatively stable over the last 3 weeks.

The number of severe pediatric infections (MIS-C) remains low and stable: 3 cases, of which 2 “untypable” and 1 omicron.

Ep 234-3: Meredith Wadman in ScienceInsider 31 Jan: BA.2 not so similar

“To what extent does a BA.1 infection protect you against reinfection with BA.2?” Zeller asks. “From what I have seen in Denmark, it’s not going to be 100%.”

2. Delta vs Omicron breakthrough infections: similar or different?  

Ep 234-4: Wratil Nature Medicine Jan 2022: another confirmation that 3 exposures to Spike protein (by 3 vaccinations, infection + 2 vaccination or 2 vaccinations + breakthrough infection) results in “high quality antibodies” with superior neutralizing capacity against all variants, including omicron.

Conclusions: 

1. Omicron displays the most pronounced humoral immune escape
2. “Hybrid immunity” in convalescents after one mRNA vaccination is not further enhanced by a second vaccination after a short time frame of three weeks.
3. In contrast, a timely spaced, second vaccination after several months further increases neutralization capacity to combat VoCs such as omicron.
4. In a longitudinal analysis there is no direct association between anti-spike IgG titers and the infection-neutralization capacity. A stepwise increase in the avidity of SARS-CoV-2 spike-specific antibodies after the first vaccination in convalescents and after the second and third vaccination in naive individuals was noted, consistent with the reported occurrence of affinity-matured memory B cells up to 6 months, highlighting that quality  is more important than quantity.
5. Triple-vaccinated naive individuals reach almost the same level of neutralization capacity against the immune escape VoC omicron as “hybrid immunity”.

Note In this paper, delta and omicron breakthrough infections provide the same level of “hybrid immunity”, which is in contrast with the next paper.

Ep 234-5: Servellita medRxiv 26 Jan ‘22

Vaccine boosting and breakthrough infections can restore broad neutralizing hybrid immunity by increasing baseline titers, with higher relative titers against the infecting variant:

• Delta-specific titers in Delta breakthroughs rose to become comparable to levels against WT,
• Omicron specific titers in Omicron BTI rose to levels against Delta, hence lower than WT

However, probably not variant is determining, but severity of disease:

moderate to severe clinical infections in both Delta and Omicron BTI associated with significantly higher neutralization titers than mild or asymptomatic infections among immunocompetent patients (p=0.022).

Implications according to the authors:

• Omicron-induced immunity may be insufficient to prevent infection from another, more pathogenic variant, should it emerge in the future.
• Highlight the continued importance of vaccine boosters in enhancing immunity, as breakthrough infection alone may not be reliable in eliciting protective titers against re-infection or future infection from different variants.
• The relative increase in immunity against the infecting variant in breakthrough infections indicates that the use of variant-specific immunogens in vaccine development remains a viable strategy for addressing VOCs that continue to circulate in the population.

Personal note: in the first wave, it was noted that the higher neut titers induced by severe infection also waned more quickly, but that may also relate to the fact that subjects with severe disease were mostly older. So clearly, we have to take into account several possible determinants

3. Vaccine effectiveness evolution?

Ep 234-6: Tenforde MMWR 28 Jan ’22: Confirmation that a third dose mRNA was superior to 2 doses with regard to hospitalization risk both in immunocompetent and immunocompromised subjects Aug-Dec 2021 (=delta period).

Third dose indicated  >5 month after 2nd in immunocompetent and already > 1 month in immunocompromised subjects.

Ep 234-7: Evolution of VE in UK 27 Jan ‘22

1e Against symptomatic infection

VE 15 against symptomatic infection 15+ weeks after booster 40-60 %:  slightly higher

• in younger versus older subjects
• in Moderna vs Pfizer boosters.

2e Against hospitalisation

VE after 10 + weeks against hospitalization: 75-90 % (better for Moderna than Pfizer booster)  

3e Against death (> 60 yrs)

Ep 234-8: Danza 1 Feb MMWR Protection by vaccination + booster against omicron in Los Angeles

4. Do we need a fourth dose and/or omicron specific vaccine?

Ep 234-9: Clare Watson Nature Briefings 28 Jan ’22 Arguments about a fourth dose mRNA

Pro: There is emerging evidence that the effect of a 3rd dose wanes over months and a 4th dose might broaden the immune response (including T cells) further towards variants to come and the effect might last longer: some data from Israel, where a 4th dose has been given to older and immunocompromised subjects.

Con:  WHO states that a vaccination strategy based on repeated booster doses of the original vaccine

composition is unlikely to be appropriate or sustainable.

Also a matter of “vaccine justice” since large parts of the world population have not received yet any vaccine or only an inactivated vaccine.

Quotes from WHO statement of 11 Jan:

• In the context of the circulation of Omicron SARS-CoV-2 Variant of Concern, the TAG-CO-VAC urges broader access globally to current COVID-19 vaccines for primary series and booster doses, in the hope that this also mitigates the emergence and impact of new VOCs.

COVID-19 vaccines need to:

• be based on strains that are genetically and antigenically close to the circulating SARS-CoV-2 variant(s);
• in addition to protection against severe disease and death, be more effective in protection against infection thus lowering community transmission and the need for stringent and broad-reaching public health and social measures;
• elicit immune responses that are broad, strong, and long-lasting in order to reduce the need for successive booster doses.

In line with this approach, there are many options to consider:

• a monovalent vaccine that elicits an immune response against the predominant circulating variant(s), although this option faces the challenge of the rapid emergence of SARS-CoV-2 variants and the time needed to develop a modified or new vaccine;
• a multivalent vaccine containing antigens from different SARS-CoV-2 VOCs;
• a pan SARS-CoV-2 vaccine: a more sustainable long-term option that would effectively be variant-proof.

Ep 234-10: Emily Waltz in Nature Briefings 28 Jan: a lot of uncertainty whether we need an omicron-specific vaccine.

Con: the present vaccine (after 3 doses) protects with 90 % efficacy against omicron hospitalization and the omicron wave will be over before the omicron vaccine will be ready for use

Pro:  a booster with the highly mutated omicron will further broaden and increase immunity for the variants to come?  (Unless the next variant has a very different mutation profile?)

5. Vaccine for children under 5?

Ep 234-11: Sharon Lafranière in New York Times  1 Feb ’22 on Pfizer vaccine for children under five.

https://www.nytimes.com/live/2022/02/01/world/covid-19-cases-vaccine#children-covid-vaccine

Two doses at 1/10 of the adult concentration gave a remarkable result:

• In children 6 months-2 years comparable to adolescents
• In children 2-4 years: “less robust”

Therefore a third dose is now being tested, but FDA does not want to wait for the results (!).

Hence: authorization will be asked to start with 2 doses and most probable the final regimen will be: second dose 3 weeks after the first, and a third dose two months after that.

Ep 234: The background is the US epidemic, which is presently much worse than in Europe.  See paper in Financial Times https://www.ft.com/content/03aa46e2-ac3a-4c16-82be-431ea4c43e58

Ep 234-11: A summary by John’s Hopkins of the very positive balance between vaccine effectiveness and risks in children.

In addition, despite the gloomy truth in the graph above, there is also a “silver lining” in the US epidemic, according to Bloomberg School epidemiologist David Dowdy:

1. Vaccines saved over 1 million lives in the US—“that’s more than the population of Austin, Texas,” Dowdy observed.
2. Public health measures overall “have done even more,” Dowdy continued. During last winter’s outbreak peak, our “collective societal action” like physical distancing helped avert “the equivalent of fifteen 777s crashing every day,” Dowdy wrote.
3. “We even accomplished this while getting unemployment back nearly to pre-pandemic levels,” Dowdy noted. Few would have predicted this a year ago.
4. The current omicron wave “didn’t even dent our mobility.” “We’re living life almost at the same level as we were before the pandemic (just with masks on, in some places,” and this is mostly thanks to the combination of “vaccination, testing, and other public health action,” Dowdy wrote.

The pandemic has been “the biggest public health threat of our time,” Dowdy concluded, and the response has not always been perfect, but viewed in a certain light, our accomplishments are incredible.

Some cautious personal conclusions:

1) The Omicron sublineages, especially BA.2, almost certainly will prolong the current wave, but there is no evidence that they are more severe or more resistant to vaccines + booster.

2) Three exposures to Spike protein provides provisionally “optimal” immunity, by affinity maturation and broadening of the immune response.  It remains less clear whether all breakthrough infection have a similar beneficial effect.  Omicron and/or mild infections may provide a weaker stimulus to immune maturation?

3) Despite weak (but still significant) mitigating influence on omicron infections, vaccine + booster has very good effectiveness against severe disease even after 15+ weeks, but there is also clear waning.

4) The debate on a fourth dose or an omicron-specific booster is ongoing.  At the same timen there is progress towards a “pansarbeco” vaccine (see Ep. 232).

5) FDA is prepared to approve a reduced dose Pfizer vaccine for children under five and most probably it  will require 3 injections.

Best wishes,

Guido