22 Jan 2022 Ep 228: T cell immunity and hybrid immunity to delta and omicron

Dear colleagues,

(For text with figures and graphs see first attachment) 

Because various colleagues asked questions about these topics, I bring some recent papers (either already mentioned or not yet) together to provide a synopsis showing that:

• T cell immunity to omicron is better preserved than Ab responses
• Before Omicron, it was shown that hybrid immunity (infection, followed by 1 vaccination) induces potent RBD specific memory B cells, with cross-neutralizing antibodies and a particular CD4 T cell imprint.
• A different type of hybrid immunity, Delta as well as Omicron breakthrough infections (= infections after full vaccination), induce very potent and broad T and B responses, suggesting that these variants could be a good basis for a follow-up booster.   

 

T CELL IMMUNITY TO OMICRON PRESERVED

Ep 228-1 (= Ep 212-3):  Roanne Keaton et al show that CD4 and CD8 T cell responses to omicron Spike, Membrane and Nucleocapside peptide pools are similar as compared to ancestral, beta and delta.   This is shown for Pfizer or Janssen vaccinated or convalescent subjects (Fig 1) as well as in hospitalized subjects in the various epidemic waves (Fig 2).  The “quality” of the response is also controlled for by looking at “polyfunctionality” (simultaneous production of various cytokines).

 

 

 

 

 

Overall, these results demonstrate that vaccination and infection induce a robust CD4 and CD8 T cell response that largely cross-reacts with Omicron, consistent with … limited T cell escape

by Beta, Delta and Omicron,

which is in sharp contrast with clear-cut and progressive escape in neutralizing antibody response.

However, this cross-sectional study give no direct evidence of protective immunity by T cells, as responses are apparently independent of vaccination or disease: they show “sensitization” to the viral antigens.

 

Ep 228-2 (= 212-4-: Very similar results presented by GeurtsvanKessel on HCW vaccinated with either AZ, Janssen, Pfizer or Moderna:

1. Antibody responses:

• High binding antibody levels against WT SARS-CoV-2 spike (S) were detected 28 days after vaccination with both mRNA vaccines (mRNA-1273 or BNT162b2), which significantly decreased after 6 months. In contrast, antibody levels were lower after Ad26.COV2.S vaccination but did not wane.

 

• Neutralization assays with live virus showed consistent cross-neutralization of the Beta and Delta variants in study participants, but Omicron-specific responses were significantly lower or absent.

 

 

• Booster partially restored neutralization of the Omicron variant, but responses were still up to-17-fold decreased compared to D614G.

 

 

2. T cell responses:

• CD4+ T-cell responses were detected up to 6 months after all vaccination regimens; S-specific T-cell responses were highest after mRNA-1273 vaccination. No significant differences were detected between D614G- and variant specific T-cell responses, including Omicron, indicating minimal escape at the T-cell level.

 

 

CONCLUSION:   T cell responses after vaccination with mRNA or Janssen Ad26 vaccines are better preserved than antibody responses, which wane more with time and are much weaker against omicron, even after an additional booster mRNA vaccine.   

 

 

 

 

 

 

HYBRID IMMUNITY before and with Omicron:

 

PRE-OMICRON (Delta)

 

Ep 228-3: Goldberg medRxiv 5 Dec 2021: Waning of infection-induced and hybrid COVID-19 immunity  

 

(Data from Aug-Sept 2021 = before Omicron)

 

Confirmed infection rates increased per 100,000 risk-days  according to time elapsed:

• For unvaccinated previously infected individuals from 10.5 after 4-6 months ago to 30.2 after

over a year ago.

• For individuals receiving a single dose vaccine following prior infection (hybrid immunity)

increased from 3.7 those vaccinated within two months to 11.6 for those vaccinated over 6 months ago.

• For fully vaccinated previously uninfected individuals increased from 21.1 for persons vaccinated within  two months to 88.9 for those vaccinated more than 6 months ago.

 

Besides the obvious waning, it is also clear that the second group with hybrid immunity  (infection, followed by single vaccine dose) showed the lowest chances on reinfection per 100,000 risk-days : only slightly lower than unvaccinated infected and 6-8 lower than double vaccinated

 

 

Ep 228-4 (= 226-15): Lauren Rodda medRxiv 12 Jan 2022 Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity

 

As compared to previously naïve subjects, those that were first infected and next vaccinated showed:

• More SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies
• Distinct population of IFN-𝛾/IL-10-positive memory SARS-CoV-2 spike-specific CD4+ T cells

 

These CD4 T characteristics are “imprinted” by infection, as they could NOT be elicited by additional vaccination and therefore are part of “hybrid immunity”.

 

 

 

 

 

 

 

 

 

 

Ep 228-5 : Tay EMBO Mol Med Jan 2022 Immunological comparison between fully vaccinated subjects without or with Delta breakthrough infection and  primary unvaccinated Delta infections

 

1. Similar plasma antibody levels (including neut) against SARS-Cov-2 wild type and Delta between vaccine breakthrough cases and vaccinated close contacts.

 

 

2. Spike receptor binding domain (RBD) antibody secreting cell (ASC) memory B cells have a higher frequency in vaccinated uninfected contacts than in vaccinated BTI.  These B cells can produce higher levels of neut Ab against WT and Delta after in vitro stimulation.  

 

 

3. CD4 T cells from vaccine BTI tended produce more IL-2 and have a more “polyfunctional” profile than those of vaccinated uninfected close contacts.  At first view, this is counter-intuitive, as these characteristics are rather associated with “protective immunity”?

 

4. Inflammatory cytokines including IL-1b and TNF were lower in vaccine breakthrough infections than primary infection of similar disease severity, underscoring the usefulness of vaccination in preventing inflammation  

 

Therefore:          RBD-specific memory B cell levels may be a correlate of protection against Delta variant infection in vaccinated population

 

 

CONCLUSION:

 

1. Subject with a single dose vaccine following prior infection (hybrid immunity) have the lowest chances on reinfection by 6 months as compared to double vaccinated, but never infected subjects.

 

2. As compared to previously naïve subjects, those that were first infected and next vaccinated showed:

• More SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies
• Distinct population of IFN-𝛾/IL-10-positive memory SARS-CoV-2 spike-specific CD4+ T cells

 

3. RBD-specific memory B cell levels may be a correlate of protection against Delta variant infection in vaccinated population

 

 

 

 

 

OMICRON and hybrid immunity

 

Ep 228-6 (= 226-13): Suryawanshi medRxiv 17 Jan 2020 Limited cross-variant immunity after infection with the SARS-CoV-2 Omicron variant without vaccination, but extensive cross-neutralization after BTI  

 

Mouse data:

• Sera from Omicron-infected mice only neutralize Omicron, sera from Delta-infected mice are broadly effective against Delta and other VOCs, including Omicron.

Human data:

• Sera from vaccinated subjects with Omicron breakthrough infection reveals very effective cross-variant neutralization  than sera from unvaccinated subjects, who recovered from Delta infection (convalescent)

 

 

 

Shown = % neutralization (Y) by increasing dilutions of sera (X) from naïve (a); delta-convalescent (b) and vaccinated omicron BTI (c)

 

 

 

 

 

B.1.1.7 = alpha;

B.1.351 = beta;

B.1.617.2= delta;

B.1.1.529 = omicron

 

 

 

 

Collectively, our study shows that

• While the Omicron virus is immunogenic, infection with this variant in unvaccinated individuals may not elicit effective cross-neutralizing antibodies against other variants.
• In vaccinated individuals, however, Omicron infection effectively induces immunity against itself and enhances protection against other variants.

 

This, together with our finding that Delta infection is broadly immunogenic in mice, supports the inclusion of Omicron and Delta-based immunogens in future multivalent vaccination strategies for broad protection against variants.

 

 

Ep 228-7 (= Ep 226-14): Hassen Kared medRxiv 13 Jan 2022 Immunity in Omicron SARS-1 CoV-2 breakthrough COVID-19 in vaccinated adults.

 

Very elegant and thorough study of Omicron and Delta breakthrough infections (BTI) in vaccinated subjects, compared to healthy donor vaccinated subjects:

 

1. In BTI increased activated CD8 T cells

• Delta BTI more spike oriented
• Omicron BTI: more non-spike (ORF1ab, ORF3 and Nucleoprotein)

 

 

2. Activated Follicular Helper T cells (TFH): B cell helpers

 

 

 

 

3. Boosted humoral responses

 

 

 

 

The rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation after omicron BTI suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity

 

In fact, this paper reinforces the conclusion of the previous one:  a combination of delta and omicron spikes, potentially in combination with other proteins, could by ideal for future booster vaccines.  

 

 

 

 

Ep 228-8: Lechmere medRxiv 21 Dec 2021: Delta breakthrough infections (BTI) in double vaccinated subjects (either Pfizer or Astra-Zeneca) induces more potent cross-neutralizing antibodies, against all variants including omicron than Delta infection in unvaccinated subjects.

 

Neutralizing titers 50 % (ID50) of plasma dilutions from  

               

Unvaccinated Delta                                        Double vaccinated Delta BTI

 

WT = wild type virus, B.1.1.7 = alpha VOC; B.1.617.2 = Delta; B.1.621 = Mu; B.1.351 = beta VOC

 

 

 

WT = wild type virus;   B.1.617.2 = Delta VOC;    B.1.1.529 = Omicron VOC

 

 

CONCLUSIONS

 

1. Infection with Omicron this variant in unvaccinated individuals may not elicit effective cross-neutralizing antibodies against other variants.

Omicron breakthrough infection effectively induces immunity against itself and enhances protection against other variants.

 

2. Delta breakthrough infections (BTI) in double vaccinated subjects induces very potent cross-neutralizing antibodies, against all variants including Omicron and Delta.

 

A combination of delta and omicron spikes, potentially in combination with other proteins, could by ideal for future booster vaccines by activating cross-neutralizing B cells and robust T cell responses to both Spike and (more conserved) non-Spike proteins.