4 Dec 2021 Episode 197 : Omicron, vaccines and T cells part 2

Dear colleagues,

The present Episode will contune the discussion on the role of T cells in infection and vaccination.  However, I will first give an update on omicron and third booster vaccine.

Omicron

Ep 197-1: Technical briefing UK Health Security Agency 3 Dec 2021

1. Suggestion of immune escape and higher transmissibility:

Structural modelling indicates that the mutations present in Omicron are highly likely to affect the binding of natural and therapeutic antibodies, and to enhance binding to human ACE2 to an extent greater than that seen in other variants to date.

2. First data on 22 English cases

• Presently unclear whether mild or severe, in relation to vaccination status
• Effect of third dose?

3. The report also contains technical information on how to detect omicron

Ep 197-2: Callaway and Ledford Nature Briefing (3 Dec 2021)

• On 1 Dec, South Africa recorded 8,561 omicron cases, up from the 3,402 reported on 26 Nov.
• According to Wenseleer (KULeuven) 3-6 X as infectious as delta.
• Many unknowns remain on disease presentation and actual resistance to vaccines.

Ep 197-3: Fabian Schmidt Nature (Sept 2021): generated a “polymutant” spike by culturing SARS-CoV-2 in the presence of convalescent plasma (Wuhan infected), resulting in 20 mutations (PMS20).

Some PMS20 mutations are common with omicron: ∆69-70, K417N; N440K; E484E/K; N501Y; D614G

The PMS20 virus was resistant against serum from most convalescent patients (as expected) and from subjects who received 2 doses of mRNA , but serum from people who were first infected then vaccinated kept good neutralizing capacity.

Ep 197-4: Smriti Mallapathy Nature Briefing (2 Dec 2021): Criticism on indiscriminate travel restrictions towards southern Africa:

Omicron already found in many countries, in people without direct link with South Africa: local spread is already ongoing for some time.

Travel restrictions are intended to buy countries time to prepare their health systems for Omicron’s potential impact. But unless they implement domestic measures, it’s hard to know what “we’re buying time for”

WHO advise: against travel bans, but testing before and after journey +  quarantining new arrivals

Ep 197-5: Elie Dolgin in Nature Briefing (2 Dec 2021):  update on the “booster debate”, with a lot of uncertainty about omicron….

Immunogenicity of third dose (not yet taking omicron into account)

Ep 197-6  : Demonbreun in medRxiv (21 Nov 2021): third mRNA dose in healthy adults

• About 20 X RBD antibody rise 6-10 days after booster, exceeding levels after natural infection with COVID-19, after two doses of vaccine, or after both natural infection and vaccination. (Is the latter sufficiently encouraging to also neutralize omicron ?)
• Surrogate neutralization of delta  high but reduced in comparison with wild-type SARS-CoV-2.

Ep 197-7: Munro in Lancet (Dec 2021) presents a very complex study on immunogenicity and reactogenicity of various third dose booster after 2 doses of either ChAd-Ox1 (Astra-Zeneca) or BNT162b2 (Pfizer).  Fig 3 shows that antibody titers rise for all boosters:  m173 (Moderna mRNA) > Pfizer mRNA > Novavax (S protein) > Ad26 (Janssen) = ChAd (AZ) = Curevac mRNA > Valneva (inactivated).  Whereas increase was 25-30 fold for Pfizer and Moderna, it was about 10 X for Novavax and 5 fold or less for the latter 4 vaccines. 

The increase in T cell responses (ELISPOT) was very limited though….

Ep 197-7 B: Tal Patalon JAMA (30 Nov 2021):  over 80 % reduction in PCR positivity after 3rd Pfizer dose in a cohort of over 300,000 HCW.    

Ep 197-7 C: Andrews medRxiv (15 Nov 2021): very similar result in England subjects of over 50, who received either Astra-Zeneca or Pfizer as 2 doses and Pfizer as 3rd dose.  

T cells

Responses to mRNA vaccine

Ep 197-8: Ugur Sahin in Nature (July 2021) shows that the Pfizer BNT162b2 vaccine not only induces neutralizing antibodies, but also IFN-γ and IL-2 producing CD4 and CD8 T cells, some of which react with epitopes that are conserved across variants and are presented by several HLA types.  These data suggest that, even if vaccine-induced antibodies are not able to neutralize a particular variant, T cells still could provide a second line of defense to mitigate infection and prevent severe disease.  

Ep 197-9 : Marc Painter in Immunity (Sept 2021) provides a more thorough analysis: after the first mRNA vaccine dose Spike-specific CD4 T cells are  induced, with either Th1 and T follicular helper characteristics. Th1 and Tfh are correlated with increase of antigen-specific CD8 T and neutralizing antibodies after the second dose respectively.   Follow-up was too short to assess the durability of these T cell responses.  

Cross-reactive and/or conserved epitopes

Ep 197-10 : Xiuyuan Lu in J Exp Med (Dec 2021) describe a “universal epitope” S864–882 (hence in S2), which is presented by multiple HLA types and recognized by a common (public) T cell receptor (TCR) and could activate T follicular helper cells (Tfh), important in maturation of B cells. Because of it’s association with mild disease, the authors propose that this epitope could be a candidate for peptide vaccines upon coupling with appropriate linear B cell epitopes, that may provide an “adjustable” booster for variants.

Ep 197-11: Priyanka Shah in Front Imm makes the case of S2, the fusion part of the Spike; as a good immunogen to elicit broad T and B responses against variants and even other coronaviruses, because it is much more conserved than S1 and pre-existing immunity (based cross-reactivity) has been shown, with readily available memory T and B cells.  However, until now, the evidence of the importance of neutralizing antibodies against S2 in protection by mRNA Spike-induced vaccination is limited.

NTD = N-terminal domain; RBD = receptor-binding domain; FP = fusion protein; HR = heptad repeat, MPER= membrane proximal extracellular region; TM = transmembrane; CyT = cytoplasmid terminal

Ep 197-12: Mallajosyula in Science Immunology (July 2021 conserved cross-reactive CD8 T cells, directed against highly conserved epitopes in polymerase and S2 are present in unexposed subjects and predominate in infected subjects with mild disease, suggesting a partly protective role

Ep 197-13 : Swadling in Nature (June 2021) show that unexposed controls have T cells reactive with SARS-CoV-2 polymerase (based on the high conservation with seasonal CoV).  As expected these cross-reactive responses are significantly increased after infection.  The important observation is, however that these T cell responses are also increased in highly exposed seronegative health care workers, who show evidence of abortive infection (temporarily increase of the interferon-induced IF127). Clearly, this observation suggests that boosting this response in uninfected subjects could be used as a vaccination strategy.     

Ep 197-14: Lineburg in Immunity (May 2021) describes an immunodominant cross-reactive CD8 T epitope in the Nucleoprotein  between SARS-CoV-2 and other beta-CoV (OC43 and HKU-1) restricted to HLA-B7 positive non-SARS-CoV-2 exposed and recovered subjects.  The clinical significance is unclear, but as the authors indicate this type of epitopes could be exploited to boost or prime the immune response in a vaccination strategy.

Ep 197-15: Wei Hu in MPDI Vaccines (Sept 2021) took another approach by analyzing T cell receptor (TCR) structure and reactivity to a set of highly conserved, but SARS-CoV-2 specific (hence non-cross-reacting) peptides: 2 peptides in each of the 4 structural proteins (Spike, Membrane, Nucleoprotein and Envelope).  These “T cell clonotypes” were present in limited frequency in unexposed subjects and expanded in vivo in SARS-CoV-2 infected patients.  In vitro stimulation of heathy donor PBMC expanded the CD8 T cells.  Although these results are very preliminary, they suggest that particular conserved non-cross reactive structural SARS-CoV-2 peptides could be used in a vaccination to stimulate particular CD8 T cells.  

SOME CONCLUSIONS

1. It seems that omicron will take over the pandemic during this Winter, in a similar way as delta did in the Spring. Both South-African and English data suggested that 2 doses of the commonly used Pfizer and A-Z vaccines will not stop the spreading. The pathogenic potential and the sensitivity to a third booster hopefully will become clear soon.

2. The third dose induces very high neutralizing titers, better than after infection + 2 dose vaccination and results in a very significant (> 80%) reduction of PCR+ and symptomatic infections, but obviously these results are on the short run and against the delta variant.

3. Conceptually T cells have a dual role in infection and vaccination:  

• CD4T follicular helper cells are crucial to induce high affinity and broad neutralizing antibodies and CD8 T cytotoxic cells can kill infected cells.  These mechanisms are clearly active during infection and early T cell responses are associated with mild disease or even abortive infection in HCW who remain seronegative.
• In the context of vaccination, the former activity is important to maintain and broaden the memory B cells, but this mechanism is clearly partly failing to protect against infection with the highly infectious delta variant several months after 2 doses. It is unclear whether the memory CD8 T cell responses have a role in the observed rather good protection against severe disease.
• It is evident that the present vaccines induce already some T cell responses to Spike, but they could be further enforced by including other whole proteins or perhaps conserved peptide sequences in the mRNA vaccine.  Several targets are being developed: the S2 (fusion) part of Spike, the polymerase, the nucleoprotein and others. 
  • Polymerase is attractive, because it is expressed very early (before any structural protein), it has large conserved parts
  • Nucleoprotein is also very conserved and very abundantly expressed.
• The question whether it is an advantage to focus on epitopes that are cross-reactive amongst beta-coronaviruses remains open.
• Focusing on T cells as a “second line of defense” after vaccination thus makes a lot of sense, but decades of attempts to develop T cell based vaccines against other conserved proteins in other variable viruses (HIV, Influenza, hepatitis B and C, Herpes…) have not resulted in clinically useful vaccines.      

Best wishes,

Guido