22 May 2021 Episode 142 Focus on T cellular immunity in COVID disease and SARS-CoV-2 vaccines

Dear colleagues,

For those of you, who are not very familiar with cellular immunology, I refer to the last section (6), with very didactic reviews.

In section 1, we focus on COVID in immune deficient patients (congenital or immunosuppressed after transplantation): as expected they are more prone to severe disease, but there is hope that at least a proportion of those who have not been infected will still benefit from vaccination. The results of vaccinating pregnant and lactating women are very encouraging.

In section 2, we focus on T cell responses after mRNA vaccination.  These responses seem better preserved against variants, as compared to neutralizing antibodies, but it is possible that subjects with some HLA types could be less protected.

Section 3 provides some arguments to include nucleocapsid in SARCoV-2 vaccines, based on favorable T cell responses to this antigen (which is not useful for antibody-mediated protection).

In section 4 the possible role of CD4 and CD8 T cells in protective immunity during COVID and for vaccine purposes is analyzed.

Section 5 briefly discusses the SARS-CoV-2 diagnostics based on T cell receptor sequencing.    

1. Disease and vaccine effects in immunity in special populations:

Ep 142-1 A:   Meyts in J Clin All Imm (Feb 2021) describes a large international cohort of 94 COVID patients with various inborn errors of immunity of which a staggering 2/3 had severe disease: (28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died).   However, not all patients suffered from severe disease: 10 were asymptomatic and 25 treated as outpatients. 

Risk factors for severe disease were as in the general population. Thus, perhaps surprisingly, the inherent immunocompromised state of the patients studied here was generally not a predominant risk factor for severe COVID-19.

But: younger male patients with IEI are more likely to endure severe COVID-19

• Many patients with defects predominantly in the adaptive immune system had rather mild disease (similar to influenza).
• Also most patients with chronic granulomatous disease, STAT-3 variant and auto-inflammatory disease had asymp or mild COVD

Ep 142-1 B: Kinoshita in J Clin Immunol focuses on a small cohort 7 pediatric and adult COVID patients with congenital antibody deficiencies  and a benign clinical course.  As compared to “healthy” controls (unaffected family members), who also contracted a mild COVID, the patients similar antibody and T cell responses.

Clearly, a proportion but not all individuals with inborn errors in immunity (IEI) are at increased risk for severe disease.  The results of Kinoshita suggest that it is certainly worth to try and vaccinate these individuals, but careful individual follow-up will be needed….  

Ep 142-2: Thieme in Transplantation shows that both T cell and neutralizing antibody responses in immunosuppressed kidney transplanted patients with COVID disease are rather similar as in controls.  The authors conclude that this raises hopes for effective vaccination in this cohort.

Ep 142-3 A: Chavarot in Transplatation however, finds a very poor response to Pfizer vaccine in 102 kidney transplant patients treated with belaracept (CTLA4-Ig): after 2nd dose less than 6 % has anti-S antibodies and only 30 % had IFN-g producing T cells (but those were at low numbers)

Ep 142-3 B:  Sebastian Dolff argues that not only the immune suppression by CTLA4 should be considered as the explanation here.  They argue that besides IFN-g also IL-2 and TNF should be measures, as dose predominate in the normal Th1 response to Pfizer.  Nevertheless the very low seroconversion rate of Ab to spike is very worrying….

Ep 142-4: Collier in JAMA on mRNA vaccination in pregnant and lactating women (and infants)

• Reactogenicity to second dose of mRNA vaccine was lower in pregnant and lactating than in non-pregnant women.  
• All antibody functions (including neut) and T cell functiins indistinguishable between mRNA vaccinated non-pregnant and pregnant or lactating women, but clearly higher than in COVID infected pregnant or non-pregnant women (median 12 days after PCR+ or symptoms)
• As expected, presence of (neut) Ab in milk and in cord blood.
• Vaccine effect against variants: Ab (including neut) slightly lower against B.1.117 (British) and much lower, but still quite positive against B.1.315 (South-African).  Remarkable no difference in either CD4 or CD8 T cell responses (IFN-g ELISPOT) against wild type or variant spike peptides.

2. More on spike-specific T cell responses to mRNA vaccines:

Ep 142-5: Neidleman et al. in bioRxiv conducted CyTOF (up to 40 markers) on antigen-specific T cells in longitudinal samples from infection-naive and COVID-19 convalescent mRNA vaccinees.

• Vaccine-elicited T cells respond identically to variants B.1.17 and B.1.315 as WT
• T cells change in quantity but not quality after second dose in uninfected vaccinees.
• Convalescents’ T cells do not need a second dose and preferentially express the longevity-associated marker CD127 and respiratory tract homing receptors. Thus seemingly qualitatively superior T cell responses

Ep 142-6: Callaghar in bioRxiv developed a whole blood assay to measure IFN-g T cell responses (similar to the Quantiferon test). 

• They show that spike-specific T cell responses to mRNA vaccines are higher than in convalescent subjects. 
• Responses in women tend to be higher and they are lower in older (> 50 yrs) subjects.
• Interestingly they find slightly lower T cell responses when peptide pools from variants are used: 85 % for variant B.1.1.7, 70.2% for B.1.315, and 83.4% for B.1.1.248.   

Ep 142-7: Reynolds in Science makes essentially the same observation with less sophisticated T cell assays.  However, they do find subtle defects in T cell responses to variants depending on the HLA polymorphism. So, it is possible that individuals vaccinated with the present vaccines may show differential susceptibility to infection with variants, based on their HLA constitution

3. More on nucleocapsid specific T cell responses in infection and as a novel vaccine component

Ep 142-8: Lineburg in Immunity

• The nucleocapsid (N) protein induced an immunodominant response in HLA-B7+ COVID-19-recovered individuals that was also detectable in unexposed donors.
•  A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response.
• T cell-mediated crossreactivity in convalescent COVID toward circulating OC43 and HKU-1 betacoronaviruses but not 229E or NL63 alphacoronaviruses.
• This selective T cell cross-reactivity for an immunodominant SARS-CoV-2 epitope and its homologs from seasonal coronaviruses, may contribute to long-lasting protective immunity, but in this case only in B7(+) individuals (about 10 % of the population).

Ep 142-9: Matchett in bioRxiv proposes Nunclecapsid as a part of a COVID vaccine. In fact they show that vaccination of either Syrian hamsters or hACE2 transgenic mice with recombinant human Adeno-5, expressing N induces protective immunity against a deadly challenge.

4. More on CD4 T and CD8 T cell responses in natural infection

Ep 142-10: Jun Sion Low in Science describes an immunodominant CD4 T cell epitope in the RBD (S346-365) that is recognized by 94 % of convalescent T cells and also multiple cross-reactive sites in S between SARS-CoV-2 and other Coronaviruses.  They conclude that both the immunodominant and cross-reactive sites could be useful in a T cell oriented vaccine.  

Ep 142-11: Bange in Nat Med shows that CD8 T cell count and functionality is a clear-cut positive factor for survival in COVID patients with hematological cancer.

Ep 142-13: Ivanova medRxiv: Immune responses in COVID disease and after vaccination may have some resemblance, in terms of neutralizing antibodies or T cell responses, but there are important qualitative differences

• Innate: a highly augmented interferon response in COVID-19 patients, largely absent in vaccine recipients. This contributes to the dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in vaccinated  subjects.
• The majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients primarily circulating memory cells.

5. SARS-CoV-2 infection diagnosis based on T cells

Ep 142-14 A:  Sheridan in Nature Biotechnology refers to a test for SARS-CoV-2 infection, based on T cell receptor (TCR) sequencing, with high specificity and sensitivity.  The principle is analogous as antibodies: SARS-CoV-2 infection will result in expansion of very specific T cell clones and skewing of diversity,  which can be picked up with very specific sequencing.  Obviously, the immune system needs some time to recognize the pathogen and expand particular T cell clones (at the expense of others), just like it is the case for B cells and antibodies    

Ep 142-14 B:  Dalai in medRxiv describes the clinical validation of this test, based on whole blood.

• Table 3 p. 15 shows that a high (>90 %) positive predictive value is reached > 8 days since PCR(+) in one study and > 15 days after symptoms onset in another
• Table 5 p. 26 shows that it performs better than serology.
• The sensitivity is excellent

The advantage is that SARS-CoV-2 specific T cell presence can be evaluated on whole frozen blood, just by PCR, without the need for specific peptides or culture.

6. Reviews for your orientation

Ep 142-15: Jarjour in Immunity provides a short overview of the different types of T cells, potentially involved in COVID immunology and stresses the importance of a well-functional T cell memory in protection after infection or vaccination, also in view of (antibody-) escape mutants.

Ep 142-16: DiPiazza in BBRC goes a bit deeper into the phenotype and function of pathogenic and protective T cell responses.

Ep 142-17: Quast in Immunity a very didactic review on how high affinity neutralizing antibodies and memory B cells are generated with re