29 January 2022 Episode 232 WHO Symposium on Pansarbeco vaccines

Dear colleagues,

For those (including myself) who missed the WHO Symposium on Pansarbeco vaccines, there is good news: most presentations are available at https://www.who.int/news-room/events/detail/2022/01/28/default-calendar/who-consultation-on-covid-vaccines-research-why-do-we-need-a-pan-sarbecovirus-vaccine

For myself and you, I made my own “synopsis” (below) and I stored all pdf on our website

Session 1 is largely introductory and contains no really new information, rather summaries on omicron with  some nice slides.  The most interesting part is Ep 232-7 on the effect of prior infection and/or vaccination in the Delta and Omicron era.

Session 2 proposes some novel vaccines that could elicit broad pan-sarbeco protection, including against animal viruses that otherwise might introduce new pandemics: 

• 232-8: Self-amplifying RNA or Adenoviruses, encoding both Spike and Nucleoprotein
• 232-9 and -11: Ferritin nanoparticles with Spike
• 232-10; A “consensus” Spike protein, based on conserved sequences, used as a boost after Pfizer mRNA
•  232-12: The concept of a T cell-based vaccine with conserved epitopes, showing “promiscuous” binding to various HLA molecules

In my opinion, the self-amplifying S + N RNA and the “consensus” Spike protein are the closest to application.

Session 3 describes the assays, needed for the evaluation of a Pansarbeco vaccine.

Session 1.  Is there a need for a pan-sarbecovirus vaccine?

Ep232-1 : Global situation of Omicron

1.Globally,the number of cases increases, largely driven by Omicron

2.Now present in almost every country

3.Has significant growth advantage over Delta

4.Relative risk of severe disease due to Omicron appears lower than Delta

5.Large Omicron outbreaks have the potential to overwhelm health services

Ep 232-2 : Severity in South-Africa

• Reduced odds of developing severe disease when compared to a period when Delta variant was dominant.   
• This also applies to children, EXCEPT 1 to 4 yrs old

Major limitation of this analysis is lack of individual sequenced data, reliable vaccination history and/or re-infection history and restriction to one geographic area.

Ep 232-3:   Overview of Sarbecoviruses

Ep 232-4: What can animal (hamster) models teach us about omicron vs delta?

• Omicron is less pathogenic than previous VOCs and associated to reduced virus titers in the Lower Respiratory Tract
• Transmission studies indicate that Omicron is highly transmissible and can outcompete the highly transmissible delta VOC in the presence of immune pressure.
• So far, animal models faithfully recapitulate pathogenesis and transmission data of VOCs collected in humans

Ep 232-5: Higgins: Vaccine effectiveness against severe disease up to Nov 2021 in observational studies: certainly higher than 70 % for both mRNA and Adenovectors

Ep 232-6: Aggarwal Vaccine Effectiveness against Omicron

• Existing vaccines (and natural infection) remains effective at preventing severe disease / hospitalization
• While vaccination, with additional doses or with prior infection, can also provide moderate protection against infection, it will not stop transmission and prevent outbreaks
• Each infection is a further chance for viral evolution, so long-term strategy needs to consider how to best reduce infections and outbreaks, even if there is no healthcare stress

Ep 232-7: Effect of prior infection (“natural immunity”) and/or vaccination on (re-) infection.

1. Delta era

Both vaccination and having survived COVID-19 provided protection

• Surviving previous infection is more protective than vaccination alone, during Delta era
• Yet initial SARS-CoV-2 infection has significant risks for severe illness, death

→ Only vaccination and staying up-to-date boosters is recommended

Very high risks for unvaccinated

• Among unvaccinated, only 20% previously diagnosed with COVID infection

→ It is essential to reach the other 80% to get vaccinated

2. Omicron era

Session 2.  What are promising approaches to a pan–sarbecovirus vaccine?

Ep 232-8: New Approaches for Accessible, Durable and Broadly Protective Coronavirus Vaccines

Four viable approaches for a pan-sarbecovirusvaccine

1. Next-generation self-amplifying(sa) RNA against SARS-CoV-2 S + N protein
2. Next-generation hAd5 DNA vaccine against SARS-CoV-2 S + N protein
3. Adjuvanted RBD protein
4. Heterologous prime –boost approaches (e.g. saRNA + hAd5

Entering Phase 1 / 2 trials in Q1 2022

Manufacturing scale up ongoing in USA, RSA and Botswana

Ep 232-9: Ferritin nanoparticles as a vaccine platform for Influenza and SARS-CoV-2 Spike or RBD

Weak against omicron!

Ep 232-10: Linfa Wang:  Highly potent pan‐sarbecovirus neutralizing antibodies induced by serial cross-clade immunization

1. SARS (CoV-1) survivor, vaccinated with Pfizer SARS-CoV-2 vaccine → produces pan-sarbeco neutralizing Ab (including against the related bat viruses.

2. Design of a pansarbeco vaccine as a “booster” for SARS-CoV-2 vaccine produced very broad neut Ab in mice

Ep 232-11: Haynes: Sortase-conjugated ferritin coupled RBD nanoparticles:

The RBD-sortase conjugated (sc)-ferritin nanoparticle (NP) induced antibodies variants of SARS

• Induced antibodies that neutralized WA-1, Alpha, Beta, Gamma, Epsilon, Iota , Kappa, Delta and Omicron variants

• Protected in monkeys WA-1, Beta and Delta variant challenges

Summary:

• SARS-CoV-2 and other Sabecovirus RBDs have epitopes that broadly neutralize current VOCs and other Sarbecoviruses.

• Goal is to evaluate current vaccines and to design improved future immunogens to these epitopes.

• Future work will design RBDs that focus the immune response on conserved epitopes, as well as define epitopes on spike S2 that induce protective responses and are conserved across many CoV groups.

• Durability of responses is key for current and future vaccines.

Ep 232-12: Anusha Nathan Towards a mutation-resistant pan-sarbecovirus T cell vaccine

Session 3.  How could pan–sarbecovirus vaccines be evaluated

Ep 232-13: Florian Krammer: Panel of viruses for neutralization assays

Panel for pan-sarbecovirus vaccine:

•A selection of sarbecovirusesfrom all clades (ACE2 and non-ACE2 binding)

•Wild type SARS-CoV-2 + selection of VoCs and VoIs +  BA.1 and BA.2 (Omicron)

•To probe the extremes

• SARS-CoV-1
• RaTG13
• WIV

•Artificial escape mutants

• E.g. PMS20 (Schmidt et al., NEJM, 2021)
• Mutants from yeast libraries (Jesse Bloom lab)

Ep 232-14: Alex Sette: Evaluation of T cell responses

Conclusions:

•T cell inducing vaccine components as a broad concept to enhance preparedness against future possible pandemics

•T cell vaccine components might be effective in preventing severe disease for coronaviruses in general and sarbecovirusesin particular

•Several groups reported initial testing of SARS CoV2 vaccine components to broaden the spectrum of T cell reactivities

•A similar strategy could be considered for several families of viruses of pandemic preparedness concern (Arenaviridae, Flaviviridae, Bunyavirales, Paramixoviridae, Togaviridae, Picornaviridaeand Filioviridae)

•Not to be seen as an alternative to antibody inducing strategies, but rather synergistic with those strategies

•A T cell inducing component could be produced, tested for safety and immunogenicity in small phase I trials, and even stockpiled, as a first line of defense from a new pandemic

Ep 232-15: Galit Alter on the importance of non-neutralizing antibodies

Ep 232-16: Lin Effectiveness of various vaccines over time:

• Dependent on vaccine type Moderna > Pfizer > ChADOx1 > Janssen
• Dependent on VOC
• NOT dependent on age (except for oldest group > 65)