CME INDIA Presentation by Admin.
Vaccination is a trick. The self-made spike proteins would train our bodies to detect and terminate any real SARS-CoV-2 infections before the virus wreaks havoc.
We waited madly for COVID vaccines. We waited for our turn to get vaccinated. We took pain to go to the vaccination centre and in spite of inner fears, we went ahead. And suppose after one month of First dose you get the opportunity to have Anti Spike antibody Test. You hoped to get tremendous antibody response and when result came, you find no induction of humoral antibody at all. It could be frustrating. It happened with me(I took COVISHIELD), it happened with my wife Dr Leena Singh who took COVAXIN. It happened with others too. – Dr N K Singh (Editor, CME INDIA).
CME INDIA Discussion
Dr N K Singh:
- I got my anti-spike antibody done after 30 days of 1st dose of Covishield (Part of COVAT STUDY).
- See my reportđ How do you interpret it?
- We are doing COVAT study, Pan Indian, on over 550 physicians and it looks 20 % are not showing Antibody response after 21 days of 1st dose. We will be able to talk more about some critical issues addressed in COVAT study in the days to come.
Dr Anand Malani MD, Sangli:
Questions raised in this case which warrants a serious discussion and a clinical trial, followed by my answers or rather thinking.
Q1 – Will a second dose really help?
Ans – Seems less likely. The first dose should generate at least some response considering the high protection rate even 3 weeks after the first dose.
Q2 – Will more boosters be needed if second dose works?
Ans – Probably yes.
Q3 – Should we consider the unmeasured cell mediated immunity in this case and attempt to measure by available means at least in clinical trials in such cases?
Ans – Yes but practically difficult even in trials.
Q4 – Should we shift to or try a new vaccine of other type?
Ans – Should be the most practical solution.
Q5 – Should antibodies be monitored routinely so as to determine best vaccination policy? Or duration between 2 doses for a particular patient
Ans – Yes. But process will become bit complicated. In clinical trials should be done.
And one more interesting scenario. Posting my report (Dr Anand Malani MD, Sangli) and questions.
And questions raised in this case? This is my report done at the end of 5 weeks post first dose of Covishield. I suffered from moderate COVID-19 in Sept 2020 first half.
Q1 – Is this purely a response to vaccine? Or a booster effect?
(Pre vaccination Anti spike antibodies were not measured prior to vaccination or rather unavailable then. And theoretically they are supposed to last not more than 4 weeks post infection)
Ans – Looks to be reinforced vaccine effect.
Q2 – When should second dose be taken or not needed at all?
Ans – It definitely will not add to the benefits if taken as scheduled by policy. Further increase in titre will be of no added advantage.
Q3 – Should second dose be guided as per antibody titres?
Ans – Yes. At least in clinical trials and then apply to general population if favourable.
Q4 – Again should antibodies be measured routinely post vaccination?
Ans – Yes
Q5 – Should I qualify to donate post vaccination plasma (theoretically equivalent to or may be superior to convalescent plasma)?
Ans – I should.
USFDA approves with some stringent other criteria out of which previous documented COVID-19 infection followed by vaccination is compulsory. Cannot understand why!? Very high titre plasma may work well if used at appropriate time.
Dr Awadhesh K Singh, DM Endo., Kolkata:
- Of course, this is booster effect of first dose of vaccine – natural infection doesnât increase that much Ab. Booster effect may go as long as 6-month data-wise – no one is sure though at the moment!
- 2nd dose may not do much at the peak thus delay as much as one can!
- Ideally 2nd dose of vaccine should be given in post Covid based on only Ab titre. Even first dose should be based on Ab titre if it is cost-effective!
- We donât have any evidence so far – but sounds good theoretically!
Dr Subrahmanyam Karuturi, Rajahmundry (AP):
- Looks like your immune system attacked adenoviral vector. Maybe you have pre-existing antibodies against adenoviruses.
- Previous trials have shown that large number of patients over 55 years of age have already circulating antibodies against adenovirus rendering the COVISHIELD and vector-based vaccines ineffective. Cell-mediated response is still working, so it is not useless at large.
Dr N K Singh:
As per reference article No 2:
- A number of vectors are derived from parent viruses that humans encounter through natural infection, resulting in pre-existing antibodies and possibly memory responses against vector antigens.
- The immune system has evolved to fight off invading pathogens, which makes viral vectors subject to immune responses that have to be blocked or avoided to achieve therapeutic transgene expression.
- Administration of viral vectors can lead to the initiation of innate and adaptive immune responses against the viral particles and gene products, leading to decreased efficiency of gene transfer or elimination of the transduced cells over time
- While there are similarities in immunity to different viruses, each vector contains its own set of activation signals, which are further modified by the environment of a specific tissue.
CME INDIA Learning Points
- Innate and adaptive immune responses to vectors vaccines constitute substantial hurdles in field condition.
- We need to point out gaps in our knowledge.
- Viral vectors share many commonalities with natural viruses but are distinctly different.
- These do differ being non-replicative, delivered in a single high-titer bolus, and introduced at an unnatural site.
- It is to be emphasised again and again that âVector particles containing viral proteins that are identical or similar to antigens that humans are exposed to as a result of natural infection may be neutralized by antibodies upon injection in some humans because of pre-existing immunity.â (2)
- It is still pleasant to know that activation of, and subsequent antigen presentation by, dendritic cells is a critical step in linking innate to adaptive immunity, leading to activation/differentiation and expansion of T cells. And even if do not develop neutralising antibodies, it can protect you.
- Adenoviral vectors are particularly potent in inducing CD8+ T cell responses, facilitated by potent induction of Th1 immunity.
- A small, NIH-supported study, published as a pre-print on medRxiv, shows that immune response to the first vaccine dose in a person whoâs already had COVID-19 is equal to, or in some cases better than the response to the second dose in a person who hasnât had COVID-19. (1)
CME INDIA Tail Piece
âScientists can draw blood from people who have received the vaccine and extract the serum (liquid) part of the blood that contains antibodies. They can then ask how well those antibodies work to prevent the virus from infecting cells in the lab. The good news, for the moment, is that the antibody responses to the virus by vaccinated people are strong. This means that even a 2-fold or 5-fold reduction in antibody recognition due to a particular variant would still be expected to be protective. As new variants of concern arise and spread, they can be tested in the lab against the blood of vaccine recipients using the same types of tests to determine the new variantâs susceptibility to vaccine-induced antibodies.â – Dave OâConnor, PhD, University of Wisconsin Medical Foundation Professor of Pathology and Laboratory Medicine, University of Wisconsin-Madison
References:
- Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine . Krammer F et al. medRxiv. 2021 Feb 1.
- Nayak, S., & Herzog, R. W. (2010). Progress and prospects: immune responses to viral vectors. Gene therapy, 17(3), 295â304. https://doi.org/10.1038/gt.2009.148.
- Jamie L.Shirley ,Ype P.de Jong, Roland W.HerzogImmune Responses to Viral Gene Therapy Vectors,Moleculat Therapy.Volume 28, Issue 3, 4 March 2020, Pages 709-722. https://www.sciencedirect.com/science/article/pii/S1525001620300022.
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Most of the discussions are on vital vector vaccine but what about response to the vaccine derived from dead virus like Covaxin.
Covaxin
[28/02, 18:46] Dr Vasanth Kumar President Elect RSSDI, Hyd: Dr NK singh I need opinion of our colleagues in a following situation.
I know of a few who did not develop IgG antibodies including anti spike protein AB even two weeks after second dose of Covaxin.
Do any of you have any experience or suggestions to such people?
Dr H D Sharan Ranchi: What could a negative neutralizing antibody test against
SARS-COV-2 25 days after the first dose and negative Covid 19 IgG 28th days after the first dose of Covishield mean?
1) The test is not properly authenticated, standardised or whatever. In simple words ,the report is wrong. But the chances of both reports being wrong is very remote.
2) The sample was not properly collected or transported to lab. Once again, in simple words, the report is wrong. Once again chances are remote.
3) More than 30 yrs of Diabetes has weakened immune response. So status is uncertain.
4) It does not matter whether Neutralizing antibodies are present or not because it is the T cell immunity which matters and facilities for measuring T cells titre are not available commercially.
5) The titre may go up after the second dose so do not delay the second dose of vaccine.
Do you know what? Just take the vaccine as national duty, keep wearing the mask and go about living your normal life with due precautions.
Anyother solution?
Spike binding IgG antibodies and Neutralizing Antibody titers.
At the start of pandemic, we were blind about what is best possible treatment for covid. But after 1 yr, we are sure about certain things like steroids, probing .etc. Similarly, we are still in early phage of vaccination. As we keep traking responses & do clinical trials, we will be more confident about immunology of covid & vaccines. Till then, vaccinating max no. of people is the only way to stop this pandemic. And that’s urgent!!
Something is wrong somewhere A survey by Baltimore University,USA says that there is a tremendous surge of antibodies post infection but here I am seeing reports here saying minimum antibodies detected in even those who had the infection
Whatever literature I have gone through I have seen that in trials they have mentioned protection rate based on clinical and laboratory documentation of Covid post vaccination . They probably havenât correlated neutralising antibody titre with efficacy rate ie. protection from Covid . That in a way makes role of second dose ambiguous.
If second dose really helps by both increasing antibody titre as well as efficacy rate, then booster doses would be helpful after specific intervals .
And if cell mediated immunity is considered to be other factor in this vaccine efficacy, then really difficult to asses the vaccine efficiency on titre alone . Also in this case role of innate immunity must be considered as the results are based on UK and Brazilian studies and hence Indian clinical trial is needed to even out role of innate immunity in our population.
Yes , I think vaccine upgradation should be constant process in this very novel viral infection.
In all still lot of study is needed it seems to have real efficient vaccine.
Could be adapative immunity with â memory â response might have worked in case of Dr Anand to get such a high titre levels. I think in his case 2nd dose might be differed as if taken now wonât be giving the booster effect and also itâs not needed as probably already his immunity has given booster response . At a later date probably when titres are reduced second dose will be really useful to stimulate memory too. However logistics about getting second dose say after 12 weeks not known in our healthcare system.
And with this thought process it is but obvious that policy can be based on titre levels if they are high . However lower titres even after 3 weeks of first dose should not preclude us from going for second dose, considering role of cell mediated immunity.
Antibody measurement and decision making about vaccines might be very difficult to apply for general population, but definitely be used in larger clinical trials before formulating the future policies.
How much plasma with antibodies post vaccination effective in plasma therapy need to be studied with trials though seems theoretically possible. Hence probably still USFDA says previous documented Covid infection is must .
While there are a gazillion Qs, here are a few thoughts.
Age is probably an independent risk factor. Ab persistence in serum is also probably tied to age. NO ONE knows how long they persist, in the first place, the Abs that is. How long are the supposed to persist ? I do not believe we have the answers. Where did you come up with the 20% figure that patients vaccinated with CoviShield do not make Abs ? If there is a publication reflecting this, DO share !
As to the Q about ‘trying a new vaccine’ I do not believe anyone knows, particularly for THAT person who did not make Abs, and if another vaccine would work. Do we know if that person had Abs to OTHER vaccines ? Is there an effect of blood type ? I do not think so but some persons with certain blood types were less likely to come down with CoVID 19. That might be a different issue, altogether.
Where is the evidence that Abs should be measured (and therefore the natural follow-up query is whether one should QUANTIFY the Ab levels and then equate that to efficacy) after receiving the vaccination ? There is no CDC guideline in the USA, as far as I know.
BTW, plasma Ab transfusions have failed to demonstrate efficacy (Convalescent plasma is ineffective for covid-19
BMJ 2020; 371 doi: https://doi.org/10.1136/bmj.m4072 (Published 22 October 2020)
The most plausible theory is that Abs that exist previously owing to memory B cells producing neutralizing Abs to the vaccine was exposed to SARS-CoV 2-like virus exposure prior (some individuals were shown to have Abs in their serum who were NEVER exposed to the virus).
Meanwhile, having Abs does not make you immune to a SECOND infection !
Talking of dendritic cells, and someone mentioned linking innate and adaptive arms (it is not like shaking hands, is it ?) activation of the T cell arm does not SPECIFICALLY require interaction w these dendritic cells for antigen presentation. Why was that mentioned ? It is confusing. Involvement of dendritic cells implies CNS penetration.
JUST to give the audience that not all is hunky-dory with Abs and ‘protection’, I will give you an example from JCV and PML. As you all know, PML afflicts the brain and is caused by the JCV that has acquired neurotropic properties owing to deletions and mutations producing the JCV-MAD1 variant. A marker of PML is the RISE of JCV Ab titers in blood and elevation of JCV index in patients on a certain drug called Natalizumab, a very common drug used in multiple sclerosis. However, JCV Ab titers do NOT protect one against PML, they SIGNAL that the worst is yet to come. So, we STOP the drug and try to offset PML. And Abs do not penetrate an intact BBB, the best I can tell. So, they offer zero protection once PML hits. Therefore, having Abs does NOT automatically you are protected in patients on that drug.
Isn’t it correct that a total of 9/1702 or 0.5% patients recd the ChAdOx1 nCoV-19 in the COVOO2 study published in the Lancet, Jan 9, 2021 ?
This includes ALL standard dose patients in UK and Brazil.
I am not sure where they published phase 3 clinical trial data for AZ (which I presume is the ‘seed’ for Covishield ?) but if these the pitiable #s, it is shockingly poor. Seems awfully low #s to calculate vaccine efficacy I would assume.