Should refusal for getting immunised be made punishable? Yes? Those not opting for, can go to Mars!

In many countries, even strongly democratic, not wearing mask is an offence – penalty may be not just paying off fines but one may be put behind the bars even, like in ‘curtailed’ democracy like Singapore! Trump and his team were trolled for ridiculing Faucci and CDC for advising wearing mask in public. So also Jair Messias Bolsonaro, the president of Brazil for the same reason. Many European nations paid heavy penalty by not complying with the advices by epidemiologists. Indian PM, Modi is praised for nudging one sixth of the world population living in India to largely comply with his pleading of wearing face masks, which could be one of the reasons for India’s successful management of the pandemic. World has come far away from wearing mask with the infection spreading its tentacles far and wide. What is the strategy now? Can we say for certain we are seeing the light at the end of the tunnel, now that the infection seems to be receding in many countries? What has the humanity learnt from this ‘dark’ episode? Has the virus gone or is it going shortly?

What is the metric to judge the phase of infection: Trend of daily number of infections or deaths? Number of active cases? Positivities in testing? Or a combination of all these?

The first and foremost is the trend of daily deaths is definitely an indication.

The next could be the trend in the number of active cases either hospitalised or home quarantined. The daily mortalities would generally be a fraction of the number of active cases, depending upon the nature of the infectious disease. For COVID-19, it could be of the order of two weeks. The actual fraction would depend upon the type of medication and immunity of the cohort. The last one in the metric could be the trend and actual number of daily infections. This is an important metric even to understand the beginning of vicious cycle. If a society is able to prevent the contagion from spreading, the war is half won. One of the ways is to force the individuals to wear the mask apart from other interventions. The other is to test and quarantine those with positive infection. Obviously the effort would be exorbitant to test the whole population in one go. Not that it is impossible – China does that once a while when the authorities even sense infection in a district! Countries like India choose statistical sampling – test symptomatic individuals and their contacts – if the positivities exceed a certain guideline number, say 10%, widen the net to reach a figure of 5%.

With this strategy, the number of cases could reach an asymptotic value and never be close to zero. Even at 1% positivity with a sample size 0.1% a day, which is mind a boggling effort in a population of even 10 million, the daily infection can be safely assumed to be at 10,000 per million, though only 100 would be counted as daily infection, 9900 would be missed out – they would be either asymptomatic or mildly symptomatic but some of them could potentially be spreading the infection. No doubt, the number would be less than 10,000, but not insignificant! Unless the positivity goes down to an extremely low figure, we cannot take it for granted that the virus is gone. One has to ramp us testing many fold to reach that to reach very low positivities, very impractical! It is conservative to assume that the number of cases in the general public at the same positivity fraction.

The present strategy of statistical sampling and testing is cost effective, long term strategy. But, it is a pain on the health system, bleeding the public exchequer. With the present optimal viable strategy, the virus would continue to linger, mutate and resurge later. Is there a way out? Yes… vaccination…

Vaccination has saved the humanity from many dreaded diseases, small pox, measles, polio, and many more. Some misguided public ‘opt’ out of the covid vaccination program. Should they be allowed to exercise this option? should they have any option at all in the first place?

Have we not learnt from the face mask experience? Whether this elixir to the humanity be shunned by some not only endangering others but also entailing unnecessary public expenditure on testing, quarantining, hospitalisation paraphernalia? Damocles’ sword would always be hanging above you and me as long as these half baked ‘illiterates’ who do not believe in science, cohabit with us in this planet. Such being the case, there is a strong reason to make it binding on everyone in the society to get vaccinated as and when called for.

Else they can go Mars!

Why are many countries queuing up with a begging bowl to India for vaccines? Why are the developed countries running short of supplies? Why is the covid infection so high in Russia inspite of a ‘Sputnik’? Why is China on a lockdown again with a threatening outbreak, inspite of not only many vaccines at their disposal, but their regulatory clearances that permit quicker access?

Vaccine manufacture is a long process that typically requires complex stages of incubation in specialized facilities, and working with “living” bacteria or cell culture. They are attenuated or modified in their functionality so that they can help the immune system to recognize and fight the true pathogens. But the manufacturing facilities are not very difficult to set up.

But even then, there are shortages – why? The answer might lie in business opportunities! Vaccine is a low return, low volume enterprise. While epidemic is once in a while phenomenon, pandemics are extremely rare! Pharma companies always look beyond the horizon – they want a ‘kill’; they would grow only if investments are made in lifelong diseases like, diabetes, hypertension, anti cholesterol etc., and not in once in a lifetime risky proposals. Covid like viral infections may not be back for at least for another three or four decades. After this vaccination, there is absolutely no market for them. Even now, for the late entrants, the picture is extremely grim!

Governments should have funded not only in research but also in building production facilities, instead of waiting for some obscure companies (Moderna etc.,) to shore up. Even Pfizer would not invest heavily and if it does, would like the costing strategy such as to cover their return of investment in the first few supplies itself. That is why their vials are irrationally damn costly. Compare this in late 1930’s: USA took a bold decision during the II world war, of investing in the whole chain from research to production in ‘Manhattan Project’ – but Vannevar Bush and FDR were at the helm at that time and not Faucci and Trump! If you don’t compare Covid fight to the III world war, then you are way off the track!

Surprised why the socialist Chinese and Russian governments have not followed that Manhattan model! Even Russia is after Reddy labs to licence its production! Except SII all others in India are small business units – how they will sustain after the covid era would indeed be a million $ question!

Credits:

1. https://www.sanofi.com/en/media-room/articles/2017/understanding-the-complexity-of-vaccine-manufacturing

2. https://www.sartorius.com/download/525728/4/mrna-vaccines-biopharma-industry-white-paper-en-b-sartorius-data.pdf

There is now frantic search for vaccine supplies. Even countries like Brazil, that shunned vaccines earlier are now scouting to source the supplies. Are there enough? Even to inoculate half the world population, close to 8 billion doses may be required. There may be just enough capacities to meet that target.

Inoculation has just started world over but countries are struggling to inoculate their subjects; as of now only small countries such as Israel and Beharin seem capable of inoculating significant fraction soon; other countries are way behind the targets: even US and UK, though are getting ravaged, have inoculated just around 2% of the population; Russia is nowhere close to its vaccine production target. The reasons range from a shortage of vaccines to vials as well as manufacturing equipment to the difficulty of maintaining the right storage temperature.

India appears to be better placed in the vaccine war: Not only on the production capacity but also on the choice of the types; it could not only meet its own requirements but could also supply to others. It has as of now approved two types, one is the vector of virus protein developed by AstraZeneca-Oxford and the other, called Covaxin developed by Bharath Biotech -ICMR, attenuated whole corona virus. Both have large production capacities within the country;

With many types arriving in the market, there is competition for bigger pie.. to establish which one is better? Also there are lot of talks about the regulatory approval processes that are apparently accused of taking shortcuts – for example, one of the key parameters of evaluation, efficacy data either not available or not up to some mark like the ones by Pfizer and Moderna approved for emergency use by USA, UK, Canada, EU etc.,

What is efficacy of a vaccine?

It is evaluated in the large scale phase-3 double blind trials, wherein the volunteers are given either the vaccine or placebo – neither the volunteer nor the hospital that gives the shots is aware of who gets what. These volanteers do their normal social life, thereafter. These cohorts are followed up for infection; in due course when the number of infections reach a thresh hold number, the number of infection in the vaccinated and placebo are identified, say p and q respectively, for example; the efficacy is evaluated as q/(p+q), in percentage. All other numbers such as protection against symptoms severity, hospitalisation, mortalities are all derived from this trials.

Is it a deviation?

If the infection is not widely prevalent, it would take a lot of time to get naturally infected. Or if the infection is deadly, then also it would entail severe loss of life before even getting approvals. Then how to evaluate quickly, under ‘emergency use authorisation‘? It is done by testing the neutralising antibodies that are generated in animal and in human. For example, In 2009 H1N1 vaccines were cleared by Indian and other regulators under similar emergency use authorisation without phase 3 trials! It may not be out of place to mention that the practise of approval for the deadly Japanese encephalitis, rabies or even seasonal flu has always been to examine only the immunogenicity data! So, one need not have to treat the phase-3 trial efficacy data as an essential pre-requisite for approval.

But is it sacrosanct?

There is a recent trend in this breakneck competition to match or better the efficacy numbers. WHO prescribes 50% shall be the ballpark criterion. The early birds, Pfizer and moderna having reported 90+%, others also tend to make claims matching that, though it is not mandatory. For example, AstraZeneca-Oxford researchers have no clue about the 90% efficacy of lower first dose that was administered to some of the volanteers of UK ‘by mistake’, compared to the 60+% to those given the full first dose. The anomaly could also be statistical because of the low numbers involved. Or it could also be scientific? Many regulators world over would simply disallow such gross misadventures and any outcomes therefrom. Could it be the immune system reacting differently? They now propose increased spacing betweeen the two doses might do ‘wonders’.

The viral vector vaccines have a peculiar problem. If the immune system is familiar with the unrelated virus used as a courier, it will attack it.

To circumvent the problem of “anti-vector immunity” and it can make a vaccine less effective, AstraZeneca Researchers now contemplate use of hetero type vaccination for booster dose based on a different vector while vaccinating with adeno types (Oxford, Sputnik), instead of the same.

Attenuated types, on the other hand, should provide better immunity as body responds to many of the vectors in the virus simultaneously! Some of the Chinese vaccines are of this type.

Moderna and Pfizer vaccines are entirely of new types, hitherto not tested in humans so far but have set very high efficacy numbers over 90+! These types require deep refrigeration storage requirements such as -70 deg C, unlike others that demand only common refrigerator freezer conditions, 2 to 8 deg C. Thus there are variety of factors that go into the choice of a vaccine, especially for emergency. Rest assured all would work, generally with minimum side effects rarely with a very very low probability of anaphylactic reactions such as the one seen in penicillin injections.

In many countries such as US, EU, etc., the virus is raging with staggering mortalities. In September also, the situation in India was grim. Obviously, there is a rush in the west to get vaccinated, but may not be in India now.

Vaccine hesitancy on the raise….especially from the Indian healthcare professionals, where about a crore will be vaccinated soon on priority. Responses from participants in this segment, reflect their concerns about the efficacy of the vaccine and fear of side effects. A recent online survey shows that 59% preferred to defer vaccination. Another interesting finding is most of them want to do antibody serum test, and decide to take vaccines only if found negative! Vaccine hesitancy even in this group is worrisome, because it percolates down to the general population easily. If herd immunity does not develop quickly in the society, the fight would get prolonged……

To win the war against the dreaded virus not only should the right vaccine be available, but also there is a dire need to inoculate the media!

Credits:

1. https://timesofindia.indiatimes.com/india/how-the-immune-system-can-be-a-vaccines-enemy/articleshow/80109956.cms?utm_medium=referral&utm_campaign=iOSapp&utm_source=email

The moot question now is when would the pandemic come to an end? At this point of the pandemic, everyone is curious to know, Would the pandemic go? According World Health Organisation, for declaring such status, there shall not be any new infection for a period of two incubation periods, for this, there shall not be any single new infection for one full month! It appears to be a daunting task. Then, what would be a practical level of ‘considering it is contained‘ in reasonable time.

As all mathematical models so far have only led the planners and policy makers down, as they are studded with many underlying assumptions. Then, why not make a considered guess, based on the observation of trends. The real world trends depict the social behaviour and the complex interaction of the population to the infection nearly perfectly on real-time basis.

By now, it is clear that the daily discharges cannot be more than 7-10% active case loads as the incubation period for this virus is 10 to 14 days. Only if the daily new infections are less than, say, 8%, the discharges would exceed new infection and the number of active case loads would reduce.

On a closer scrutiny of the data from many Indian states, the number of daily new cases has already been seen to be just around 8-10% of the active case loads. It is seen that happening in larger states, like Bihar, Andhra and Telangana, where the active cases has tapering. This is evident, for example, in Orissa and Jharkhand: with nearly 44 and 37 million population respectively.the active case loads have stabilised at 2500 and 1500. The positivities are less than 2%! One could get still lower daily cases few days after ramping up the testing and isolation; but it is unviable and infeasible at such low positivity rates. Presently, sharp decreases are noticed prominently only in states with high case loads.

With this model, one can expect the active case numbers to reach an asymptotic value of something like 40 to 50 per million population for India in a reasonable time frame of say a couple of months or so. With this value, it would be approximately around 50-60k active case load for the whole country on an average. At that point of time, the daily infection rate would be 4-5K and daily mortality at around 30 – 50. Presently it is at 280K, 25K and a 250 respectively. Essentially it means, you have to be contended with one fifths of today’s figures when the virus can be assumed at reasonable control!

It is a Damocles sword with sporadic infection with a possibility of 4-5 in a million! Though it is a low risk scenario, the virologists would like nothing less than its eradication. These numbers would linger at that level whatever you do, until vaccination is done. So, don’t expect to get a ‘nil’ report! Until herd immunity with vaccination is reached, there is always a lurking danger of resurgence of this virus in some mutated form or the other! Those who don’t, are culpable of being not only hosts for the ‘demon‘ but also are facilitators of its mutation that cause immense havocs! It may not be even criminal to tag them ‘anti-socials‘!

Continuing present management measures seems to be the only viable solution as most of the larger states are already on the path of control, barring a few; While the late entrant Kerala, though has very low mortalities, has puzzled with its disproportionately high new infections. Only Maharashtra and WB are problem states. Relax while all these states reach their limiting numbers, it is only a question of time….

It may also be academically interesting if the government launches large scale sero surveys along side vaccination to understand the curious sharp fall in new infections! This would confirm the suspicion of the country having reached near herd immunity! There can’t be any other reason other than significant fraction already having got infected near the threshold herd immunity requirement. That is why Kerala reports now a large number of cases. But with uncertainties of the antibody counts that are monitored going down couple of months of infection, but immunity building up with T and B cells, that are not tested, one would not be able to draw any meaningful conclusion with such sero surveys. May be if they are also included in the testing strategy, it would be a very useful data for the future generation, as such infections are not going to be infrequent!

We have learnt many hard lessons in this nasty war: viruses can only be fought with cultural moderations of social interactions and non pharmaceutical interventions but not by allowing it to was through the community as that would entail many loss of loved ones; Vaccines would not take years to counter them. But one thing is certain, there is no end date fo this Third World War if many are unwilling to immunise!

The bottom line is, We are not that ignorant as we were once in ‘Spanish flu‘ times, also, neither the viruses are now, it is evolution!!

Oxford vaccine conundrum – in phase 2 studies, to assess the safety and immunology, studies were conducted with two different doses containing different quantity of virus particles of the vaccine[Low dose, LD: 2·2 × 10^10; Standard dose , SD: 3·5–6·5 × 10^10] to assess the immunological effectiveness of doses; the results indicated no strong difference between LD and SD. Also there was an increase in general in the antibody titres after the second dose [1]. Though they could have gone with LD itself, since even aged volunteers tolerated SD well, they decided to go with SD for phase 3 trials.

But, by mistake a significant number of people in a vaccine group were given LD as the initial dose. When they realised the mistake, they administered SD to the rest. The second dose, booster was SD for both all. Based on the infection data, it was surprisingly found [2], that efficacy is much higher in LD/SD group than the SD/SD.

LD/SD: efficacy estimated is 90·0% in a cohort size of 2741, (the infection in vaccinated is three vs 30 in the placebo group); SD/SD: efficacy estimated is 62% in a cohort size 8895, (infected in vaccine group against placebo group 27 vs 71);

The mistakenly delivered half-dose regimen appears to be more effective but was only given to ‌2,741‌ ‌subjects. Given the size of the group, differences between the demographics of the half- and full-dose cohorts and the lack of an accepted mechanistic explanation for the better efficacy, it is possible the 90% figure is an anomaly that will fail to stand up to a more rigorous assessment of the regimen.

In phase 2 studies, it may be seen that LD dose was not tested in older volunteers. So, to extend the results of LD/SD in the rest of the group to the aged is not a scientifically acceptable proposition. So, they have started a new phase- 3 trial in US with LD/SD regimen.

It is not just that: In this backdrop of Oxford vaccine’s curious contradiction of findings of higher effectiveness of LD/SD than the SD/SD regimen, scramble of permutation and combinations dominate the vaccine ‘science’. The crux is the ‘researchers’ don’t even have a ‘hypotheses’ leave alone established ‘theory’ to ‘explain’ a lower initial dose – higher booster dose effectiveness. But they also don’t want to discount the ‘findings of serendipity’ to possible statistical errors….

It is reasoned that possibly the first shot makes the second shot ineffective! Even this, still lacks the explanation – then why a lower first short could be more effective? The explanation apart, the vaccine researchers are trying to combine the different vaccines to boost the efficacy (may be mRNA’s magic 95% is the trigger, that makes them crazy to improve their numbers)!

In trying to pep up the AstraZeneca-Oxford University vaccine’s 62 percent efficacy found in the early analysis, a combination proposal from Russian authorities has been prompted [3]: The reason attributed to the lower immunity is that AstraZeneca uses the same Chimpanzee adenoviral vector for the two doses. In contrast, Sputnik V vaccine which claims 95 percent efficacy uses two different human adenoviral vectors for two shots, called as ‘heterogeneous boosting’. Russian researchers say by combining the vaccine with Sputnik V will further boost the efficacy of AstraZeneca-Oxford University‘s vaccine. The question now is, why at all to combine a vaccine having a much lower efficacy of 62%, with 95%! Though they have already started millions with Sputnik, Russian researchers probably want a foothold of acceptance by the west!

The UK government recently announced that it will begin a clinical trial combining the adenovirus vaccines with mRNA technology. AstraZeneca is also exploring heterogeneous combinations of different adenovirus vaccines.

If you wait a little longer, you may get a magic ‘concoction’ at the end… or a disgraceful acceptance of defeat by the Oxford researchers of their goof ups! Why not gracefully accept 62% figure and declare ‘take it or leave it‘! Unfortunately, the other vaccines have raised the expectation bar, which used to be only around 60% like other flu shots, to well over 90%!

Credits

1. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32466-1/fulltext

2. https://doi.org/10.1016/S0140-6736(20)32623-4

3. https://www.moneycontrol.com/news/business/companies/astrazeneca-to-initiate-human-testing-to-assess-its-covid-vaccine-with-russias-sputnik-v-6217451.html?fbclid=IwAR3F39TCzE1ZR6szsNYZtZKvq-cwtfupR6dNaovIsmSmv_TIgxA1IQvBqbc