# RKS: COVID-19 VACCINE PROTECTION - An Elusive Boon?

# RKS: COVID-19 VACCINE PROTECTION

- AN ELUSIVE BOON?

1st August 2022

THE VACCINE MANIA YET MARCHES ON ...

ANSWERS TO QUESTIONABLE PROTECTION ARE STRANGELY NOT BEING PURSUED!!

Dear Reader,

Has the coronavirus wave abated? Yes and surely so. But it has far from vanished. Nearly 230 countries are yet reporting daily COVID-19 cases and God has been considerate that the infection at present is due to a kinder Omicron variant of SARS-CoV-2 virus [novel coronavirus type 2 (nCoV-2)]. Statistics reveal presence of near 25 lakh (2.5 mn) active cases globally, and 50k are critically ill, as of last week of July 2022. (https://www.worldometers.info/coronavirus/)

If the Indian perspective is to be elaborated then there are less than 2 lakh active COVID-19 positive cases, and lesser than 1000 patients have severe disease - as per data reported in July 2022. (https://www.worldometers.info/coronavirus/)

The 'corona' victim today meekly states, rather than inquires, from his friendly family doctor, besides announcing to his near and dear ones with a smile (instead of a worrisome look) - 'I have even taken the booster!'

The national and international medical bodies, the healthcare industry and even the medical professionals - instead of finding suitable answers to this unexpected occurrence, remain gagged spectators and continue encouraging booster shots of COVID-19 vaccine. It is strange in the current era of knowledge boom that the patients and consumers are lapping up advices regarding need for vaccination, including booster shots, sans any questioning or cross-checking digitally! Seemingly there is a mass hysteria driving the continual urge to get the protective pricks against this 2019 pandemic-causative coronavirus.

COVID-19 VACCINE

At present 4 out of 100 Indians have received a booster shot compared to 40 Americans out of 100! Incidentally, Chile has the highest number of booster recipients - near 100% of its population is triple vaccinated! But, YET, both Chile as well as the US have 2.5 – 2.75 lakh active cases of coronavirus infection today - as of last week of July 2022 captured figures. 

Why? Why? Why?

VACCINE FAILURE?

Let's dwell into the protective ability of various vaccines, which is otherwise documented as their effectiveness. The most common vaccines - namely, small pox, hepatitis B, measles-mumps-rubella (MMR) and tetanus vaccines, provide near 100% protection. However, the yearly advocated flu shots is claimed to protect the adult population by 77%. What about the COVID-19 vaccines then?? These have not been proclaimed to be protective BUT at best have been documented to reduce symptoms, including disease severity, by approximately 76%! 

COVID-19 vaccines have seemingly failed to provide complete rock-solid shield against the SARS-CoV-2 virus since 30% of the sufferers have even taken the 3rd 'protective dose'. (https://www.thehindu.com/news/national/kerala/covid-19-survey-shows-30-of-respondents-who-had-taken-third-dose-vaccine-contracted-disease-during-third-wave-in-india/article65357795.ece) 

Since the promised antibody boost is seemingly elusive in many individuals it would be enlightening to dwell into reasons for low immunity even after vaccination. Amongst the many that could be blamed, the following seem to be most decisive:

• Old age
• Suppressed immunity due to diseases or drugs
• Continual consumption of alcohol post-vaccination
• Genetic factors

The reasons for weak immune system in old age is lessened production of the protective B-cells and T-cells [type of white blood cells / corpuscles (WBC) (also called leukocytes)] by the bone marrow of the senior citizens.

VACCINE EFFICACY MECHANISM

WBCs are of 3 types:

1. Granulocytes: Eosinophils (react in allergies, but also fight against bacteria and parasites), basophils (participate in allergies), neutrophils (first responding immune cells)
2. Lymphocytes: B-cells (B-lymphocytes), T-cells (T-lymphocytes) (fight specific antigens - meaning identified any invader previously encountered - whether virus, bacteria or an allergen)
3. Monocytes: Clean up dead cells, including in our tissues (by monocytes in blood entering tissues and converting to macrophages)

Fighting a specific bug such as SARS-CoV-2 requires the recruiting of lymphocytes. Hence, irrespective of the vaccine type, the attempt to protect the body via COVID-19 immunity-enhancing shots reflects on the functioning of B-cells and T-cells. When the SARS-CoV-2 virus enters the human body, especially in those vaccinated or previously exposed, it is first 'greeted' by T-cells and then channelized to the B-cells. 

• T-cells constitute 60-80% of the WBCs. Their job is to jail the virus and transfer it to the gallows, meaning the B-cells.
• B-cells constitute mere 10-20% of WBCs. They manufacture antibodies which in turn attaches to the virus transferred by T-cells. The ensuing antigen-antibody complex formed is then destroyed by monocytes and macrophages via the process called phagocytosis.

• Memory T-cells constitute 10% of T-cells. [PLoS Pathog 2008; 4(4): e1000041] If the antibodies are inadequate, the Killer T-cells themselves phagocytose the invading virus and most die during the fighting. The surviving T-cells end up as 'memory' T-cells.

Memory T-cells tend to remember the enemy and when the SARS-CoV-2 attacks again they more promptly evoke a fighting response. However, they have a limited lifespan of 1-5 months and their pool is replenished by only 10% every week. Thus, the body relies on the presence of antibodies for a longer-term immune status.

ALL ABOUT ANTIBODIES

The B-cells when first exposed to the virus differentiate into plasma cell subtype which manufacture antibodies. After the infection is resolved the plasma cells vanish from blood; however, the B-cells remaining behind turn into memory B-cells. The latter can persist for years or even a lifetime.

Memory B-cells have a menu card of listed antibodies whose production it dictates. Although the plasma cells vanish from blood after infection is cured, many of them remain for long periods in bone marrow as Long-Lived Plasma Cells (LLPC) or, also referred to, as memory plasma cells. The latter do not divide and persist for months, years or even a lifetime to ensure continuous supply of antibodies. 

ANTI-SARS CoV-2 SPIKE PROTEIN ANTIBODIES

When a specific SARS-CoV-2 virus enters the memory B-cells directs the plasma cells to develop specific antibodies that can act as patriotic missile and target the specific invader. These are known as 'Anti-SARS-CoV-2 Spike Protein Antibodies' since they target the protein-containing spikes present on the surface of COVID-9 causing virus.  

It is the spikes present on the SARS-CoV-2 that facilitates its invasion into the human cells and thereby initiate the infection. The Anti-SARS-CoV-2 Spike Protein antibodies are thus the best effective in destroying the virus since they target the primary hit point of the bug.

THE MEMORY B-CELLS

Many infections occur at body surfaces, such as the skin, airway passages, intestinal tract and genital tract. Notably, the vast majority of memory T-cells are preferentially present at these sites - far outnumbering memory T cells in the circulation and all internal organs combined. 

When a virus invades, the T-cells latches on the same and present to the B-cells which are then activated to produce plasma cells. Both the B-cells and plasma cells once exposed to the virus memorize the same and now these cells are respectively labelled as memory B-cells and memory plasma cells (respectively). B-cells are of two subtypes:

1. Memory B-cells: These react more promptly to T-cell presented 'same' antigen to generate more plasma cells. Memory B-cells DO NOT produce antibodies. 
2. Memory Plasma cells: The memory plasma cells stores a compendium of antibody portfolio. Depending upon the specific invading antigen, antibodies are manufactured ONLY to neutralize that particular virus or bacteria ('infective bug'); hence, when the SARS-CoV-2 enters the body, after either a COVID-19 infection or 'the' vaccination, the memory plasma cells having captured the culprit virus specifications in its menu card, produces specific "Anti-SARS-CoV-2 Spike Protein Antibodies" to neutralize the novel coronavirus-2019 (nCoV-2019).
3. The memory plasma B-cell produces thousands of anti-SARS-CoV-2 spike protein antibodies per second!

Now what are these antibodies? What types of antibodies we harbour within us? This needs to be crystal clear if one has to ascertain the true protective merits of vaccination against the SARS-CoV-2 virus.

IgG vs IgM

Antibodies are actually protein molecules called Immunoglobulins (Ig) and these are exclusively manufactured by B-cells which the bone marrow makes over the lifetime. There are total of 5 varieties of immunoglobulins, namely IgA, IgD, IgE, IgG & IgM. The 2 important and relevant antibody types that are stimulated, when a virus like SARS-CoV-2 attacks, include:

1. IgM: These antibodies are produced within 4-7 days as the first response by memory plasma cells in those vaccinated, or re-exposed to the virus. 
2. IgG: When the IgM concentrations decline after 2-3 weeks, IgG commence their appearance in blood and peak in 2 weeks. It is IgG which is maintained at a high levels for a very long period - since memory plasma cells are long-lived and secrete antibodies for months, years or a lifetime.

Why memory plasma cells can survive for years together is because they tend to hide in appropriate niches of the bone marrow for several months at a stretch! 

IgG SUBTYPES

Amongst all the antibodies present IgG is most plentiful and constitutes to 70-80% of the total blood antibody concentrations (titre). IgG itself has 4 subtypes.

Thus, the anti-SARS-CoV-2 spike protein antibodies are actually IgG and the subtypes would be a mix of IgG1 and IgG3. When the protection against SARS-CoV-2 is to be quantified it would be the IgG1 and IgG3 components' assessment that matters, and not the total IgG concentrations.

QUANTIFYING ANTIBODIES AGAINST SARS-CoV-2

There are two antibodies which can be evaluated to detect immunity build up against SARS-CoV-2. [Microbiol Spectrum 2021; 9: e00247-21]

1. Antibodies directed against SARS-CoV-2 specific nucleocapsid (NC) antigens. Presence of these antibodies is specific and easily detectable in early infection. However, Anti-SARS-CoV-2 NC antibodies do not persist long enough to signify previous infection or provide long-term protection against COVID-19.
2. Anti-SARS-CoV-2 spike protein antibodies function as neutralizing antibodies and are most relevant to estimate for predicting immune prowess against the COVID-19 causative virus. 

Antibodies against spike protein of novel coronavirus-2019 target the receptor (Receptor Binding Domain) of the spike via which the virus otherwise latches on to the human cells to initiate the COVID-19 disease. Although both IgG1 and IgG3 predominate as a response to SARS-Cov-2 antigens, there is more anti-spike IgG1 than IgG3 detectable on testing. 

The electrochemiluminescence sandwich immunoassay (ECLIA) to determine anti-spike antibodies (S-Ig) seems to be the most reliable and results ranging from 0.4 to 508.0 arbitrary units (AU) per millilitre (mL) have been reported in those vaccinated. Some interesting marker outcomes to dwell upon are:

• The severe and critical cases develop less anti-SARS-CoV-2 antibody response INITIALLY than those with mild-to-moderate disease. 
• Following hospitalization, and post-discharge, it is the severe COVID-19 patients who will have higher concentrations of anti-SARS-CoV-2 antibodies as compared to those having suffered milder disease.
• In those fully vaccinated (2 doses) the levels of Anti-SARS-CoV-2 Spike Protein antibodies can be 10,000 AU/mL.
• In those double vaccinated but have suffered previous COVID-19 infection, the concentrations could even reach 30,000 AU/mL!  

From an individual's perspective, the following data is relevant: [Eur J Cancer 2021; 154: 4-6]

• 21% of patients with positive RTPCR will not demonstrate S-Ig.
• Amongst those demonstrating an initial negative response, 61% will display antibodies (100 AU/mL average) after 1st vaccine dose and 86% after the 2nd dose. 
• Amongst the 62% rest of population who demonstrate positive S-Ig test when infected, the overall antibody concentrations are 150% higher following vaccination.

Screening for specific antibodies facilitates customising dosing of vaccine and dictating the interval gap between the doses.

SUMMARY

The body has 2 long-term defence mechanisms against already experienced invaders: memory T-cells and memory B-cells.

WHY ARE T-CELLS NOT THE BEST OF DEFENCE OPTIONS?

For a synchronized memory T-cells and memory B-cells driven protective immune system to operate successfully, the lymphocyte population must be adequate and the infection should have a long incubation period. 

• The thymus gland in neck is a primary production site of T-cells. Every year till the age of 45 years the thymus degenerates by 3%; thereafter it is 1% on yearly basis till death. Thus, as one grows older, the elderly have a compromised immunity because the T-cells have become insufficient in number.
• It must be mentioned that the memory T-cells persist for 30-160 days, and only 10% are replenished weekly leading to attrition in its count over a long-term.
• Incubation period refers to the time lag between occurrence of symptoms and the first invasion of the bug (virus, bacteria) inside the body. It is considered short or long depending on whether it is less (short incubation period) or more (long incubation period) than 7 days. Since memory T-cells are generally deficient, and new T-cells get activated only 20 hours of sustained stimulation by the virus, the immediate fighting power on account of T-cells is compromised.
• SARS-CoV-2 has also been blamed to cause T-cell exhaustion and/or impaired memory T-cell generation in select COVID-19 cases. 

In light of the above, whether T-cell memory is actually important for durable protective immunity against SARS-CoV-2 is a legitimate question. At a minimum, T-cells may provide a second arrow in the quiver of immunological memory. [Immunity 2021; 54(1): 14-18]

PERSISTENT PRESENCE OF ANTIBODIES THE BEST BET

Memory B-cells take 3-4 days to stimulate plasma cells to produce antibodies. Hence, since the SARS-CoV-2 virus has apparently a short incubation period there is a need for antibodies to be pre-existent if COVID-19 disease is to be assuredly protected against. 

It typically takes approximately two weeks after vaccination for the body to produce an immune response. 

BE WISE

Since the actual protection is mediated by neutralizing the virus by antibodies, the latter are most crucial in immune defence mechanism.

It is thus, not only logical, but more than sensible, to ascertain the protection perceived to be afforded via vaccination by doing a quantitative immunity check up in the laboratory - rather than fantasying a protective dome against coronavirus around oneself post-vaccination. The goal of vaccination is to prevent infectious disease. Many notable, highly effective vaccines have been designed in an empirical way, with full understanding of how and why they work only arriving later. In many ways, the successes achieved by vaccines have been against the ‘easy’ pathogens - those that do not vary much, hide from or rapidly disable the immune system. 

The SARS-CoV-2 virus is continuously mutating, affects multiple loci in body and even known to negatively impact T-cells. It is truly challenging for a vaccine therefore to afford reliable protection against the this COVID-2019 causing virus. If there is to be a true reassuring protection against the SARS-CoV-2 then CONSTANT presence of adequate antibodies is a must.

Don't run after vaccination - check one's specific antibody levels (against the spike protein of SARS-CoV-2) and determine the underlying protection that is already in existence. Remember that those previously infected, AND protected by high antibody (S-Ig) concentrations, do not usually get re-infected. 

Further, there are reported possibilities of precipitating diseases linked to hyperimmunity - popularly known as 'autoimmune disorders' following taking vaccines aimlessly and rampantly as a result of mass hysteria. Be wary. 

The Health authorities do not talk about regulating vaccine doses based on antibodies' estimation since the world does not murmur on the same. The world health organizations do not talk about the same since even the most advanced countries do not offer to the public tests for detecting anti-SARS-CoV-2 spike protein antibodies. The evidence for unawareness of health authorities, whether domestic or overseas, is that there is no fixed defined interval between two doses, and even in-between the last dose and booster, or for subsequent booster. The debate has been continuous regarding the same and there have been not only varying recommendations - country-to-country, but even changing stances of fixing interval period between two consequent shots, as in India.

We Indians are genius and always ahead in technological innovations; and one large multinational and across-country laboratory does offer the mentioned tests for S-Ig detection for even the common citizen. All of us need to check and decide if we do require vaccine boosters and if we do the testing every month the timing of additional vaccine shots can be fine-tuned for each individual. Such steps will most likely eliminate hiccups and surprises.

Wishing happy times ahead with more confidence affording protection against the nCoV-2019.

DR R K SANGHAVI

Prophesied Enabler

Experience & Expertise: Clinician & Healthcare Industry Adviser