Don't care about antibodies. Let's care for innate immunity; T cell and macrophage.


I think vaccination development to create antibodies against SARS-CoV-2 is unyielding since some of the recovered patients didn't have antibodies according to the early Chinese study. If we include asymptomatic patients, the number of recovered patients without antibodies would be the majority.


The reliable antibody test in Japan shows only 0.6% for Tokyo and 0.4% for the Touhoku district. 0.6% for Tokyo is 10 times of the PCR tested patients and 0.4% of the Touhoku district is 100 times of the PCR tested patients. What do these facts mean?

  • There are many more infected people than we can trace by PCR testing, which applies to all countries.
  • The rate of antibody generation varies by region ten times or Touhoku PCR test tracking is one-tenth of the Tokyo region.
Well, the only single point is that we cannot get the whole picture of this disease by antibody testing.

No evidence but from my own experience and hearing, I guess that around 20% of people in Tokyo have infected. There are many people around me saying "I had a cold lasting longer than a usual one this season."

The below is the result of the question "Have you had a cold which seemed to be COVID-19 since November 2019?" on twitter to Japanese people. I don't say I can quantify from this but I think we can say there are many people (from 10 to 40%) had a cold live COVID-19 already.

Antibody tests or antibody-creation vaccines will not solve this COVID-19 pandemic at all.


Then, let's look at the other factors than antibodies.


There come a few papers that CD4+ and CD8+ T cells can fight with SARS-CoV-2 and 34-60% of non-exposed individuals have those T cells that react to SARS-CoV-2 before this pandemic. I think these facts are the key to solve this pandemic.


Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

https://www.cell.com/cell/fulltext/S0092-8674(20)30610-3
Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.

T cells found in COVID-19 patients ‘bode well’ for long-term immunity

https://www.sciencemag.org/news/2020/05/t-cells-found-covid-19-patients-bode-well-long-term-immunity
Thiel and colleagues analyzed blood from 68 uninfected people and found that 34% hosted helper T cells that recognized SARS-CoV-2. The La Jolla team detected this crossreactivity in about half of stored blood samples collected between 2015 and 2018, well before the current pandemic began. The researchers think these cells were likely triggered by past infection with one of the four human coronaviruses that cause colds; proteins in these viruses resemble those of SARS-CoV-2.

Those papers mention that past infection with the four common human coronavirus cold may trigger those T cells creation.

I agree with this to some extent but not wholly. My disagreement points are
  1. There are people who often catch a cold and people who seldom do. The former people don't have enough innate immunity to a (coronavirus) cold and the latter have enough innate immunity to a (coronavirus) cold. 
  2. It is said that human coronavirus cold is more common in Asia than the rest of the world and some people say this may make people in Asia more immune to SARS-CoV-2. Wait a second. Then, why is common human coronavirus more common in Asia every year? If people in Asia are more immune to human coronavirus, there should be less or at lease decreasing human coronavirus patients in Asia. This contradicts.
  3. Why death rate of Japanese in West Europe or North America is one-hundredth of Asian American/European? Most of them live there for long years.
I believe BCG/TB is the key to strengthen T cell responses. Please google "BCG T cell". You can find many papers such as below.

Mycobacterium bovis BCG Vaccination Induces Divergent Proinflammatory or Regulatory T Cell Responses in Adults
Mycobacterium bovis bacillus Calmette-Guérin (BCG), the only currently available vaccine against tuberculosis, induces variable protection in adults. Immune correlates of protection are lacking, and analyses on cytokine-producing T cell subsets in protected versus unprotected cohorts have yielded inconsistent results. We studied the primary T cell response, both proinflammatory and regulatory T cell responses, induced by BCG vaccination in adults. Twelve healthy adult volunteers who were tuberculin skin test (TST) negative, QuantiFERON test (QFT) negative, and BCG naive were vaccinated with BCG and followed up prospectively. BCG vaccination induced an unexpectedly dichotomous immune response in this small, BCG-naive, young-adult cohort: BCG vaccination induced either gamma interferon-positive (IFN-γ+) interleukin 2-positive (IL-2+) tumor necrosis factor α-positive (TNF-α+) polyfunctional CD4+ T cells concurrent with CD4+ IL-17A+ and CD8+ IFN-γ+ T cells or, in contrast, virtually absent cytokine responses with induction of CD8+ regulatory T cells. Significant induction of polyfunctional CD4+ IFN-γ+ IL-2+ TNF-α+ T cells and IFN-γ production by peripheral blood mononuclear cells (PBMCs) was confined to individuals with strong immunization-induced local skin inflammation and increased serum C-reactive protein (CRP). Conversely, in individuals with mild inflammation, regulatory-like CD8+ T cells were uniquely induced. Thus, BCG vaccination either induced a broad proinflammatory T cell response with local inflammatory reactogenicity or, in contrast, a predominant CD8+ regulatory T cell response with mild local inflammation, poor cytokine induction, and absent polyfunctional CD4+ T cells. Further detailed fine mapping of the heterogeneous host response to BCG vaccination using classical and nonclassical immune markers will enhance our understanding of the mechanisms and determinants that underlie the induction of apparently opposite immune responses and how these impact the ability of BCG to induce protective immunity to TB.

Memory T Lymphocytes Generated by Mycobacterium bovis BCG Vaccination Reside within a CD4 CD44lo CD62 Ligandhi Population
In the lungs of mice vaccinated with Mycobacterium bovis BCG, there was an accumulation of CD4 cells expressing the activated effector phenotype CD44hi CD62 ligandlo (CD62Llo) which were capable of secreting gamma interferon. Upon cell transfer, however, cells expressing a resting/naïve phenotype (CD44lo CD62Lhi) were capable of protecting the recipients from a virulent challenge infection, suggesting the emergence of T-cell memory from within this subset.

Another big factor seems to be macrophage. BCG/TB activates macrophage significantly.


Please check the Youtube video below by a Japanese doctor. You can see how our body battle with SARS-CoV-2 without B cell antibodies. His explanation is simple and clear. However, the auto-translation to English on YouTube doesn't work well. I hope someone can translate this correctly. This worth listening to.


 

(Added on 23 May)
There is a paper on Nature saying monocytes and macrophages are the keys to stop critical conditions. T cell is mentioned, too.

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

https://www.nature.com/articles/s41577-020-0331-4


I started to learn immunity two or three weeks ago and I have been amazed (and overwhelmed) by how our immunity is complex; multi-layers/stages, inter-relational, etc and there are many more things we don't know yet.

But, when it comes to immunity to an infectious disease, I felt a strong discomfort with the fact that only the antibodies produced by B cells are used to judge our immunity. Where did the various layers, circuits, and multiple stages go? If the flu is R0=2.5 and 60% of us get infected every year, aren't we seeing a population decrease? There are many infectious diseases and human beings should be coming to extinct.


We have more layers to protect our body and in this case of SARS-CoV-2, macrophage and T cell activated by BCG vaccine/TB seem to be the keys.


(Added on 28 May)
Below is the chart Dr. Miyasaka used in his Facebook post. I totally agree.





It's time to spend on BCG or BCG-related vaccines. VPM1002 seems promising since it seems easy to produce massively.

If you have read my previous posts, you know that the BCG Tokyo strain seems to be the most effective strain. I found a recombinant 72f BCG vaccine from the BCG Tokyo strain. This may be the most effective for SARS-CoV-2 and might be easier to produce rapidly.

https://www.jstage.jst.go.jp/article/jsci/31/5/31_5_356/_pdf
I hope Dr. Masaji Okada who has been working on this is called to solve this COVID-19 pandemic.

https://nrid.nii.ac.jp/ja/nrid/1000040160684/

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