16 Sept 2022 Episode 287 Epidemiology; RBD vaccines and children

Episode 287: Epidemiology, vaccination in children and RBD vaccines

Dear colleagues,

Don’t worry, this episode will be “lighter” than Ep 286…

• Slow re-emergence of the epidemic in Belgium and UK: which are the viruses, severity etc. Also data on infection- and vaccine seroprevalence from Canada
• Interesting Cuban and Chinese vaccines based on receptor-binding domain (RBD).
• Some nice papers from Hong-Kong, Canada and US on effectiveness of vaccination in children.
• As a bonus, two papers with a broader perspective….

PAR 1. Epidemiology

Ep 287-1:  Sciensano report of last week (in Dutch, no Eng version): after declining figures, we see a first rise in new infections.  BA.5 is dominant (94 %) and 2 “minority species BA.4 (4.3 %) and BA.2 (1.6 %).  Second booster has started: already almost 50 % in 85+. (I got mine on Wednesday).   

Ep 287-2: UK Health Security Agency Technical Briefing 45 of 9 Sept 2022

• While BA.5 is still dominant, with sublineages (BA.5.1; BA.5.2 and BA.5.3) and BA.4 well represented, there are two new variants in UK:
  • BA.4.6 (additional mutation R346T) already 3.3 %
  • BA.2.75 and sublineages still limited to 100 cases in total

• Especially BA.5.2 and BA.4.6 have growth advantage over BA.5

• Severity of BA.4 and BA.5 in UK patients (chance on hospitalization) is similar to BA.2
• Severity of BA.2.75 not evaluated in UK report, but may be higher. 

Ep 287-3: in HAMSTER MODEL:

Higher lung titers (left graph) and lung lesions (right pictures) than BA.5, but lower than Delta (= B.1.617.2):

• • More Inflammation in alveoli of BA.2.75 and Delta infected than BA.5 (see 4th  row right)
  • Also more virus (red dots) in BA.2.75 and Delta than BA.5 §see 2nd and 5th row)

Ep 287-4: Danuta Sowronski:  Evolution of seroprevalence by infection and vaccination over time in Canada

Grey bars= vaccine effect; black bars = by infection

Infection-induced prevalence in younger people increases mainly between sept/Oct 21 and March 22 = Omicron BA.1/2, while in older people mainly between Mach and July/Aug = BA.5

Surveillance case reports under-estimated infections

• by 12-fold between the 6th-7th and
• 92-fold between the 7th-8th snapshots

PAR 2. RBD VACCINES

1. 1. Cuban vaccine ABDALA

Ep 287-5: Limonta-Fernandez in New Biotechnology Aug 2022: C-RBD-H6 PP  = N331-K529 of the spike protein, (based on Wuhan strain) flanked by additional N- and C-terminal segments that contain polar and flexible linkers rich in Glycine and Serine, produced in Pichia pastoris yeast system, with Alum as adjuvant. 

Sequence: NWSFFSNIGGSSGGSNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKKGGSGGSSSSSSSSSSIEHHHHHH  (residues in bold = N and C extension)

Purification and test scheme

Results of immunization of non-human primates: Induction of both higher neutralizing antibodies Convalescent serum (Fig 6 ) and strong Th1 type T cell responses in spleen and lungs (Fig 7.

Ep 287-6: Hernandez-Bernal medRxiv 10 Sept: Phase 3 with C-RBD-H6 PP   = ABDALA-3

Set-up: 50 µg RBD intramuscular in 3 doses (0-14-28 days) with > 20,000 active and placebo each March-April 2021

Result:  within 50 days after third dose

- 92 % effective against symptomatic disease;

- 5 critical patients: all in placebo: 4 died

1. 2. Chinese Vaccine NSVI-06-09

Ep 287-7: Yi Liang Cell Disc Feb 2022:  A mutation-integrated trimeric RBD with broad protection against SARS-CoV-2

= Hybrid immunogen hetero-trimer RBD protein with  sequences from prototype (Wuhan), Beta and Kappa

Immunization with hybrid immunogen compared to homo-trimer (prototype)

→  induces higher neutralization titres against prototype, delta and beta

Immunization with hybrid immunogen compared to saline

• Protects against challenge with all three SARS-CoV-3

Ep 287-8: Jin Zhang ELife Aug 2022 Mosaic trimeric RBD induces potent neutralization against omicron and other SARS-CoV-2 variants

In addition to the above “variant” trimer, the same group now developed a mosaic, where eight mutations, key to certain variants are introduced into the RBD trimer as follows

Applying this mosaic trimeric RBD as a booster to mice primed with BBIBP-CorV (inactivated vaccine) resulted in higher neutralization titers against a range of variants, including omicron subvariants. (as compared to a booster with homo-trimeric prototype RBD or BBIBP-CorV)  

Ep 287-9: Nawal Al Kaabi medRxiv 6 Sept 2022:  Safety and immunogenicity of a broad-spectrum mosaic vaccine as a booster dose against SARS-CoV-2 Omicron and other circulating variants

Set-up: NVSI-06-09 (20 µg mosaic trimeric RBD as in 287-7) and BBIBP-CorV are both produced by Sinopharm CNBG

They were used as a booster in subjects who received 2 or 3 doses of BBIBP at least 8 months before

Results: Safety = OK. Immunogenicity: clearly much higher neutralizing titers by the NVSI than BBIBP against prototype (Wuhan), Omicron (BA.1, BA.2, BA.4, BA.5), Beta and Delta.

CONCLUSION

1. The Cuban RBD protein ABDALA is based on Wuhan strain and showed high protection during phase 3 in April 2021, when presumable alpha and beta (but not yet delta or omicron) were circulating.
2. The Chinese RBD has evolved into a “mosaic” trimer protein NVSI-06-09, containing key mutations of several variants. Its efficacy has not yet been shown in people, but it is promising as a booster to the inactivated vaccine: it induces high cross-neutralizing titers, including against delta and omicron subvariants.

PAR 3. Effectiveness of vaccines in children

Ep 287-10: Dan Yu-Lin NEJM 7 Sept Effectiveness of vaccination and infection on OMICRON infection in children USA

887,193 children 5 to 11 years:

•  193,346 SARS-CoV-2 infections  between March 11, 2020, and June 3, 2022;
  • 309 were hospitalized,
  • 7 have died
• 273,157 children  at least one dose of the BNT162b2 (Pfizer) vaccine

15 hospitalizations and no known among the 273,157 vaccinated children: clearly better than in non-vaccinated

As expected:

• Vaccination was less effective against the omicron variant than against delta
• Effectiveness of the vaccine was higher among previously infected children
• Waning of protection over time

The rapid decline in protection against omicron infection that was conferred by vaccination and previous infection

provides support for booster vaccination.

Ep 287-11: Rosa Duque medRxiv 8 Sept 2022: Effectiveness of BNT162b2 and CoronaVac against pediatric COVID-

19-associated hospitalization and moderate-to-severe disease in Hong-Kong.

Set-up: VE for children aged 3-11 years vs adolescents aged 12-18 years at the population level during the Omicron BA.2 wave (Jan – April 2022), using an “ecological design” leveraging the HK vaccination coverage statistics and public hospital records.

As expected:

• VE higher for Pfizer than CoronaVac (= inactivated): min 2 doses of CoV needed
• VE in children and adolescents similarly high.

Estimate of averted hospitalization: 68 for children and 999 for adolescents.

PAR 4: BONUS

Par 287-12: Carina Sagau Imunity Oct 2022 The pre-exposure SARS-CoV-2-specific T cell repertoire determines the quality of the immune response to vaccination

This paper shows that the quality of pre-existing T cells in the “naïve” repertoire is predictive of the strength of the response to the vaccine: naïve T cells have a higher expansion potential, with higher avidity (= functional affinity for Spike) and more IL-21 production, which is needed for high quality antibody production.

Immune ageing is associated with expansion of a “memory” phenotype, which lacks those characteristics and therefore results in poor antibody quality, and rapidly waning immunity after vaccination.

Ep 287-13: Final Report of the Lancet Commission on COVID-19. 

For most of us, it doesn’t contain a lot of surprises, but it is a good reference document.

That’s it for this week.

Best wishes,

Guido