17 March 2022 Episode 250 News on vaccines, viral evolution, post-COVID and Hong Kong

Dear colleagues,

According to our website, the very first episode was posted on 18 March 2020.  The world has changed a lot over the last two years, but, just like then, I can still admire the profusely blooming magnolia in my garden from my study room, while I was preparing this 250th episode. 

With many thanks to Patrick Spits again, I was triggered to explore various topics.

• The new plant-based Canadian vaccine.  Although it is not superior to any other one, it could help the people who are suspicious about the mRNA vaccines and it could be deployed in places where ultra freezers are not available.
• While the first reported cases of “deltacron” were lab artefacts, there is now more convincing evidence of recombinants, but they are not taking over the epidemic (as yet). 
• We all know some people with long-COVID complaints, including the infamous “brain fog”. The Nature study on potential brain damage after COVID is rather frightening in this regard, but it needs to be confirmed.

And what happens in Hong Kong?  

Par 1 News on vaccination

Ep 250-0:  Regev-Yochay NEJM 16 March 2022: Limited effect of fourth RNA dose in HCW in Israel

• Maximal immunogenicity of mRNA vaccines is achieved after three doses and that antibody levels can be restored by a fourth dose.
• Low vaccine efficacy of fourth dose against infections in health care workers, as well as relatively high viral loads suggesting that those who were infected were infectious.

Thus, a fourth vaccination of healthy young health care workers may have only marginal benefits. Older and vulnerable populations were not assessed.

Ep 250-1: Chunfeng Li Nature Immunology March 2022 Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine

After secondary immunization of mice, BNT162b2 induced

• A tenfold greater magnitude of antigen-specific binding and neutralizing antibodies, and potent germinal center (GC) B cell and T follicular helper TFH responses.
• there was a strikingly high magnitude of antigen-specific CD8+ T cells in the lung and spleen,
• Also enhanced innate immune responses, including enhanced plasma IFN-γ concentrations, enhanced activation of dendritic cells (DCs) and myeloid cells in the draining lymph nodes (dLNs), with a potent transcriptional signature of interferon-stimulated genes (ISGs).

Fig 8 gives a nice overview

1. At 6 h to 7 d after BNT162b2 prime, various subsets of dendritic cells (DCs) and macrophages in draining lymph nodes take up the vaccine and express spike proteins. These innate cells are highly activated and produce cytokines, including IL-6, IFN-α, IFN-γ, MCP1 and MIP1b. This activation is induced by mRNA which triggers an intracellular receptor (MDA-5), which results in type 1 interferon.
2. At days 7 to 21, strong germinal center B (GC B) and T follicular helper (TFH cell) responses are induced in B cell follicles. The CD8+ T cell response is increased mildly in both spleen and lung tissue.
3. At days 1 to 3 after boost, much more IFN-γ is produced by NK, CD4+ and CD8+ T cells, contributing to the enhanced innate cell activation after boost.
4. At 21 d after boost, the antibody response, CD4+ and CD8+ T cell responses increase significantly. The MDA5–IFNAR1 signaling pathway is essential for CD8+ T cell responses in both spleen and lung tissue.

Together, these results suggest that induction of type 1 IFN within hours after vaccination and type 3 IFN (IFN-g) after 1 day are essential mechanisms in the induction of strong immune responses to mRNA vaccines. 

Ep 250-2: CoVLP =  new COVID vaccine, based in virus-like particles (VLP) and produced in plants

VLP = second approach: just the Spike protein without genetic material, which self-assembles into VLP

1. Press release: “Covifenz” from Medago Co in Quebec has been approved 24 Feb by Health Canada.

It showed an efficacy of 71 % (even 75 % against infection, by delta “of any severity”), but is provisionally only approved for 18-64 years old (because too few 65 + in the phase 3 trial).  

2. Phase 1 study (Nat Med June 2021) provides more info on production: by transfection of Nicotiana benthamiana (tobacco) plants using Agrobacterium tumefaciens, carrying the SRARS-CoV2 “ancestral” Spike gene.

Two adjuvants AS03 and CpG1018 were compared with no adjuvant. 

Two intramuscular injections of 3.75; 7.5 or 15 µg 21 days apart were compared

• • Tolerability was OK

• • Neutralizing Ab after 42 days with AS03 superior to CpG1018 and more than 10 X convalescent level, but NOT VLP dose-dependent

• • lso very strong type 1 (IFN-g) and type 2 (IL-4) T cell responses with AS03 (equally dose-independent)

3. Primate challenge study (CMI Feb 2022) shows that 2 doses of 15 µg with AS03 is superior:

• Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF)
• Fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs
• Reduced levels of proinflammatory cytokines and chemotactic factors in the BALF
• No clinical, pathologic, or virologic evidence of vaccine associated enhanced disease was observed in vaccinated animals.

4. Phase 3 trial (medRxiv 28 Jan 2022)

• Efficacy in preventing PCR confirmed symptomatic COVID cases
• Not conclusive for 65+,  Asian, Black people; severe cases (low numbers) and also in seropositive subjects

• Variants: clear activity against gamma and delta (together 90 % of all sequenced cases), less sure for other variants (few cases). 

5. Phase 2 in older people and co-morbidities: (medRxiv Oct 2021): very similar immune responses →likely to be protective, but will have to be shown in phase 3

6. Fertility (Reprod Toxicol Feb 2022):  Lack of effects on female fertility or pre- and postnatal development of offspring in rats after exposure to AS03-adjuvanted recombinant plant-derived virus-like particle vaccine candidate for COVID-19 .

Conclusion:  The VLP approach has delivered successful vaccines in the past, including hepatitis B and Human Papilloma Virus.  Therefore, it may be more acceptable for subjects, who distrust mRNA and vector vaccines.  In addition, VLP are stable at refrigerator temperature.

The safety profile seems OK, but the efficacy  seems lower than that of mRNA vaccines, more in the range of the vector vaccines, despite seemingly very robust T and B cell responses.  

Its activity against omicron and the duration of protection need to be evaluated.  

Par 2 SARS-CoV-2 evolution and pathogenicity

Ep 250-3: Nyberg Lancet SSRN Lower pathogenicity of omicron versus delta

• Substantially lower risk for Omicron compared with Delta, with higher reductions for more severe endpoints;
• Significant variation with age:  (low) risk of hospital admission in children <10 years of age did not differ significantly by variant, while 60-69 year-olds had an approximately 75% reduced risk of hospital admission with Omicron compared with Delta.

Explanation:

reduction in intrinsic severity (in unvaccinated individuals) counterbalanced by a reduction in vaccine effectiveness.

Booster vaccination with mRNA vaccines maintains over 70% protection against hospitalisation and death in breakthrough confirmed Omicron

Ep 250-4: Markov in Nature Reviews Microbiol once again argues that there is no scientific reason to believe that the next VOC will be “benign”, because, unlike viral immune escape and transmissibility, which are under strong evolutionary pressure, virulence is typically a by- product.

The lower severity of Omicron is nothing but a lucky coincidence — compared with previous VOCs, the majority of which featured increased virulence.

We need to scrutinize the mechanisms generating highly antigenically divergent variants and the circumstances underlying their emergence. This includes studying patterns of antigenic evolution in immunodeficient individuals or

in SARS- CoV-2- permissive animal species at human proximity.

Summary figure

Ep 250-5 A: Bolze medRxiv 12 March 22 Evidence for SARS-CoV-2 Delta and Omicron co-infections and recombination

Upon sequencing almost 30,000 SARS-CoV-2 Nov21-Feb 22:

• 20 co-infections of which 1 showed low level recombination;
• 2 different independent 100 % recombinant viruses (5’ delta and 3’ omicron).

Ep 250-5 B: Coldon MedRxiv 16 March: 3 Delta-omicron recombinants in South of France.

Interestingly, in this case the Spike is a recombinant:

• N-terminal domain (NTD). enlarged, flattened, and more electropositive, characteristic of the Delta 21J/AY.4 NTD, potentially facilitating binding to electronegative lipd rafts on plasma membrane
• Receptor binding domain (RBD) is clearly inherited from the Omicron 21K/BA.1 228 variant The consequence is also an increase in the electrostatic surface potential, potentially facilitating interaction with the electronegative interface of the  ACE-2 cellular receptor.

Ep 250-6 A and B:  Reports from UK on “deltacron”

So far, samples of deltacron have been identified mostly in Europe. As of Wednesday, there have been 36 samples of deltacron reported in France, eight in Denmark and one each in Germany, Belgium and the Netherlands, according to GISAID.

Provisionally, these delta-omicron recombinants have no strong epidemic potential

Par 3 Post-COVID

Ep 250-7: Douaud Nature 7 March 2022:  SARS-CoV-2 is associated with changes in brain structure

Repeated brain scans in 785 UK Biobank participants (aged 51–81, including 401 cases who tested positive for

SARS-CoV-2 before second scan (on average 147 days after diagnosis of SARS-CoV-2):

1. More reduction in grey matter thickness and tissue-contrast in the orbitofrontal cortex and parahippocampal gyrus,
2. Greater changes in markers of tissue damage in regions functionally-connected to the primary olfactory cortex; 
3. Greater reduction in global brain size.

Associated with cognitive decline : cases needed more time to accomplish to standardized numeric (trailA ) and alphanumeric (trail B) tests

These mainly limbic brain imaging results may be the in vivo hallmarks of

• a degenerative spread of the disease via olfactory pathways,
• neuroinflammatory events,
• or of the loss of sensory input due to anosmia

Implication to be investigated:

• Hallmark of the spread of the  pathogenic effects, or of the virus itself in the brain?
• Prefiguration of a future vulnerability of the limbic system, including memory?

Ep 250-8: Rathmann Diabetologia Feb 2022: comparison for incidence of diabetes after COVID or other acute upper respiratory infection (AURI) in cohort of 70,000 people in Germany

Ep 250-9: Tejerina BMC Infect Dis: High proportion of persistent virus in subjects with non-specific complaints

Thirty patients during first wave (May-June 2020) with persistent complaints (fatigue, muscle pain, dyspnea, inappropriate tachycardia, and low-grade fever) 39–67 days after mild to moderate COVID: 51% were positive in at least one RT-PCR sample (plasma, urine, or stool):

Par 4: Hong-Kong versus Singapore and New-Zealand   

Taken from Ep 250-10 (Genomic report of Belgium 15 March 2022) and originally Financial Times  https://www-ft-com.ezp-prod1.hul.harvard.edu/content/6e610cac-400b-4843-a07b-7d870e8635a3

Clearly, the high case fatality rate in Hong Kong seems linked to the high proportion of unvaccinated elderly.

Best wishes,

Guido