Anxiously awaiting the arrival of Ms. Right

For all those anxiously waiting for the arrival of a good vaccine so we can get readily inoculated and start the process of methodically cutting the transmission of the SARS-CoV-2 virus (most likely almost all the billions of humans on Planet earth) the news that two of the six major clinical trials have ben paused was bad news indeed. However, we must analyze these facts with the proper scientific light to understand.

In an article dated September 8, 2020, Katherine J. Wu and Katie Thomas informed the NY Times readers (like yours truly) that: “pharmaceutical company AstraZeneca halted large, late-stage global trials of its coronavirus on Tuesday because of a serious suspected adverse reaction in a participant, the company said.” As we discussed in our previous article, that clinical event was a case of transverse myelitis in a British participant that the researchers eventually determined was a coincidence and not an adverse effect of the studied vaccine. The clinical trial was resumed. However, the scientists in charge of the review board in the USA have not yet authorized the re-start of the same.

On October 12, 2020, Virginia Hughes, Katie Thomas, Carl Zimmer and Katherine J. Wu (her, again?) wrote an article in the NY Times saying: “Johnson and Johnson has paused the large late-stage clinical trial of its coronavirus vaccine because of an ‘unexplained illness’ in one of the volunteers, the company said on Monday.” We still do not have any information about that incident as it is under review at present. In their website, the company said that: “following our guidelines, the participant’s illness is being reviewed and evaluated by the ENSEMBLE independent Data Safety Monitoring Board (DSMB) as well as our internal clinical and safety physicians.”

We understand the natural reaction of so many people, including us for a brief moment, of despairing about this temporary setback, as we are all scared of the tragic consequences of the pandemic in our societies and tired of the Social Isolation. After that initial deception, we must understand that those trials were stopped precisely because the system of safety safeguards of the clinical trials does work. Whenever there is a major adverse clinical event, the administrators say, “hands off” and everybody along the long process of scientific evaluation must stop it quickly. Patients are still monitored but there is no drug administration until further notice. The institutional review board (composed of entirely independent scientists and clinicians) will take all the needed time to check each nook and cranny of the trial.

On October 16, 2020, Albert Bourla, Chairman and CEO of Pfizer, said in an open letter that: “we are operating at the speed of science. This means that we may know whether our vaccine is effective by the end of October. to do so, we must a certain number of COVID-19 cases in our trial to compare the effectiveness of the vaccine in vaccinated individuals to those who received a placebo. since we must wait for a certain number of cases to occur, this data may come earlier or later based on changes in the infection rates.”

Last Monday we were watching CNN at early dawn when Rosemary Church, its lovely presenter with a plum accent, announced that British scientists of the Imperial College were about to start a clinical trial that might provide the definitive answer as to whether a vaccine candidate has immunogenicity or not: a Human Challenge COVID study.  They chose19 previously immunized young participants that would be expressly exposed to the SARS-CoV-2 virus to determine whether their acquired immunity is sustainable for a certain period of time or not. Bravo for these heroes!

There is widespread skepticism about the safety of a future vaccine(s) in the USA, especially among various Minority communities that discreetly feel they are being used as “guinea pigs” to advance research. This cautious attitude might start to allay their reasonable fears, one step at a time. Congratulations for these corporate “johnny-come-lately” but nonetheless “never-too-late” opportune exercises in a long-in-coming Cultural Sensitivity prurience.

Like the lovely lady of this tableau, we are all anxiously peeking through the window for the arrival of Ms. Right. We intentionally used the Ms. article as “la vacuna” (vaccine) has a feminine gender in the Castilian language.

Note – The feature image, Déjà from Alfred Stevens 1862-1864, was taken from Wikimedia Commons..

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What do you think? Please tell us.

Don’t leave me alone.

Inborn errors of Immunity determine lethality of COVID-19

The COVID-19 pandemic has already claimed the life of more than a million human beings worldwide and the terrible human, social, labor, and economic consequences have not abated at all, changing our daily lives forever. The clinical manifestations range from an innocuous “cold syndrome” to the grave respiratory cases; the infection fatality rate ranges from 0.1% to 0.9% and the risk factors seem to be old  age, being male and co-morbid conditions like hypertension and diabetes.

However some patients, including younger people that do not carry the risk factors, seem to be especially susceptible to the infection, which has baffled the clinicians. Considering that some other grave respiratory diseases like Influenza pneumonia were shown to prey on some clearly defined genetic abnormalities of humans, several scientists and clinicians from many countries have established a virtual space called the COVID Human Genetic Effort to test the hypothesis that the lethality of the SARS-CoV-2 virus might be enabled by monogenic inborn errors of immunity.

In an article recently published in Science, Quian Zang, from Rockefeller University in New York City, Paul Bastard, from the Necker Hospital for Sick Children in Paris, and a long list of collaborators, genetically tested 659 patients with life-threatening COVID-19 pneumonia to find out if they showed the “rare variants of loss-of-function (LOF) at the 13 human loci known to govern TLR-3 and IRF7-dependent type I interferon (IFN) immunity to influenza virus.” First the investigators tested the hypothesis that the same genetic abnormalities that determine the increased lethality of Influenza Pneumonia might have a similar effect in grave COVID-19. They recruited 659 patients—74.55men and 25,5% women, 13.9% of whom died—from various ethnic and socio-economic backgrounds, aged between one month and 99 years; they had all been hospitalized due to life-threatening pneumonia.

They initially studied three loci—TLR3(6), IRF7 (7), and IRF9 (8)—that had been already shown to be mutated in patients with symptoms of Influenza pneumonia. They also studied 10 loci that had shown mutations in other grave viral infections. “We showed that PHA-driven T-cell blasts (PHA=-T cells) from patients with AR or AD IRF7 deficiency had low levels of IRF7 expression. We then isolated circulating plasmacytoid dendritic cells (pDCs) from a patient with IRF7 deficiency. These cells were present in normal proportions, but they did produce any detectable type I or III IFNs in response to SARS-CoV-2…” They found a relatively higher importance of the deficiency in the type I IFN production compared to type III IFN. They found the presence of neutralizing auto-antibodies against type I, but not type III IFNs in other patients with life-threatening COVID-19 pneumonia. Their studies suggest that “there might be type I IFN-related genes in other patients with life-threatening COVID-19 pneumonia. They also suggest that the administration of type I IFN may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection.”

The tragic pandemic has spurred the creative imagination of thousands of scientists and clinicians across the world, which will bring innovative therapies to cure it. The addition of genetic based – therapies looks promising enough to foster their study.

What do you think? Please tell us.

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Genomics guided drugs for Asthma

Some of the scariest experiences of our childhood in Montevideo, Uruguay, involved the sudden onset of dyspnea in the middle of the night, which made us gasp for air and scream for help. Fortunately, we could count on two caring parents that quickly burst into our room and proceeded to sit us up in bed, perform some maneuvers and give us a bronchiolar anti-spasm medication (the albuterol inhalers did not exist yet)

Asthma is basically an inflammatory disease that drastically remodels our airways, which provokes shortness of breath and wheezing due to the airway obstruction and hyper-responsiveness; it represents the leading childhood disease in developed nations and affects approximately 400 million people worldwide. Catastrophes like the wildfires in the state of California at present, will only exacerbate its incidence. The interaction between environmental factors and the genetic make-up of patients complicate their long-term treatment, with 5-10% of patients out of disease control.

In the past three decades, extensive research has identified the genetic risk factors for the disease, which consist of single-nucleotide polymorphisms (SNPs); they are genetic variants with an allele frequency of 1% in the general population. To allow the genotyping, and identification of the genes of the SNPs, an innovative assay technique called Genome-Wide Genotyping was designed in 2002; as a result, the Genome-Wide Association Studies (GWASs), that could involve thousands upon thousands of participants, were made possible, shedding light on Asthma genetics. In 2007, Moffatt et al. published a paper reporting that the genetic variation of chromosome 17q12-21 was associated with Childhood Asthma; asthma-associated SNPs in this locus were eventually associated with mRNA expression of ORMDL3 in lymphoblastic cell lines using eQTL mapping. Many more SNPs were later found.

In a paper published in The Lancet Respiratory Medicine, Zaid W El-Husseini et al. updated the list of 128 independent asthma-associated SNPs, which had been discovered mostly in populations of European descent; they emphatically argued that more studies of Non-European populations are necessary to study the genetic causes of Asthma. They said that: “Approximately 88% of the disease-associated variants acquired from GWASs reside in non-coding regions. eQTL analysis is able to identify genetic variation that is involved in gene expression withing a particular tissue or cell type. An SNP within a gene or in close vicinity (within 1 Mbp) of the gene that is associated with gene expression is called a cis-eQTL…161 target genes were significantly to the top asthma SNPs in one or more studies with 154 unique target genes and seven genes overlapping.” What is the utility of this information?

The authors proposed that the asthma target genes are clustered in networks that act in sync to provoke Asthma and that, if identified, can get a downstream intervention. Considering that drug development is a long, costly and risky endeavor, the authors state that: “For a drug to be effective, it needs to be targeted to a protein involved in the causal pathway of the disease or to a physiological repressor of such a casual pathway…A biomarker highly associated with the disease but not part of the causal mechanism is therefore not an appropriate drug target. GWASs can identify genes that causally implicated in a disease and thus provide a robust technique to validate existing targets and unveil novel drug targets.”

Considering the heavy financial and resource burden of developing brand new drugs, scientists and pharma companies are engaging in the search of drug repositioning. Drugs that were initially designed, or are being studied for, another disease might be eventually repurposed for another one, based on sophisticated genetic studies. Out of the 142 asthma target genes that the authors studied, 22 were also targets of drugs for other conditions, either approved by regulatory authorities or being developed. They claimed that the genetics-targeted approach might be useful in 3 scenarios:

  1. It could identify individuals with a risk genotype related to a target for an already available drug, which would facilitate their responses to it.
  2. The discovery of an Asthma risk allele might identify a biomarker to find the best candidates for a certain treatment.
  3. The genetic studies of sub-groups of patients might identify clinical features that are idiosyncratic to them, furthering the targeting of specific drugs.

The eventual treatment responses might vary amongst individuals and for the same patient in different circumstances, depending on time-specific and tissue-specific specific epigenetic effects, the local inflammatory conditions, the contribution of transformed tissue, as well as tissue specificities and the drug’s tissue concentration. Even though the genomic studies have contributed to drug repositioning in Asthma, the authors stated that the functional annotation of many Asthma genes is missing.

The authors said: “Finally, for many asthma genes, associated pathways are missing because the emergence of functional evidence is lagging behind gene discovery. Multi-disciplinary research that integrates genetic findings, functional evidence, and therapeutic intervention might offer a way to move forward in developing much-needed asthma therapies.”

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What do you think? Please tell us.

Don’t leave me alone.

 

 

 

Vaccine hesitancy undermines fight against SARS-CoV-2


The decisions of governments in under-developed nations and the Aid organizations to carry out critically needed infrastructure projects are usually finalized in cities far away from the regions.  If they quickly build a bridge across an African river to benefit the local population, the latter will never “see it as theirs.” They might even refuse to use it in spite of the evident convenience to facilitate their mobility. Absent from their collective imagination, they view it as an extraneous artifact that was “parachuted down in their reality” by anonymous bureaucrats and do not feel they have a stake in it.  In his book Les Damnées de la Terre, Frantz Fanon, a French physician, philosopher and political activist, said that citizens must first start imagining their “need of a bridge” and then discuss details with their representatives of how to remedy it . If they are engaged in that process from the start, they will cooperate in its build-up and maintenance.

A similar situation will arise if the governments just inform their population that a vaccine for SARS-CoV-2 is ready and they should line-up for its administration. The suspicion, and even overt resistance, against vaccines in general has been sadly building up in the modern nations, fueled by shady political and business interests. On September 12, Natalie Allen, an anchor at CNN International, interviewed Dr. Heidi Larson, director of the Vaccine Confidence Project based in London. They have been studying data from almost 140 countries to determine confidence in them. At the end of the interview she precisely made that point, saying that now is the time to engage the local entities like civic institutions, religious organizations, etc., in order to make the common citizenry feel that “they have been consulted in this task.”

In an article recently published in The Lancet, Alexandre de Figuereido, Clarissa Simas, Emilie Karafillakis, Pauline Paterson and Heidi Larson reported the results of their “large-scale retrospective data-driven analysis, we examined global trends in vaccine confidence using data from 290 surveys done between September 2015 and December 2019, across 149 countries, and including 284,381 individuals.” They divided their project as follows:

  1. One country (the Philippines) was surveyed over six different timepoints.
  2. Thirteen countries were surveyed over four timepoints.
  3. Twenty-eight countries were surveyed over three timepoints.
  4. Forty countries were surveyed over two timepoints.
  5. Sixty-seven countries were surveyed only once.

With the collaboration of Gallup International, the European Commission, the Philippines Survey and Research Center, and Wellcome, they used online, telephone and face-to-face interviews to determine the participants’ perception of the Public Health importance, safety, and effectiveness of vaccines. The responses to the three statements were measured on Likert scales ranging from “strongly disagree” to “strongly agree.” The researchers used previously published data on vaccine confidence collected since 2015 from almost 250,000 participants and the survey responses collected in 2019. The researchers found that:

  1. Argentina, Liberia, and Bangladesh had the highest estimated percentage of respondents strongly agreeing that vaccines are safe in late 2015 whereas Japan, France and Mongolia had the lowest.
  2. Ethiopia, Argentina, and Bangladesh had the highest percentage of those agreeing that vaccines are important in 2015, whereas Turkey, Morocco and Georgia had the lowest.
  3. Ethiopia, Argentina, and Mauritania had the highest percentage of respondents who strongly agreed that vaccines are effective in late 2015.

“Between November 2015 and December 2019, we estimate that vaccine confidence fell for all three elements of confidence in Indonesia, the Philippines, Pakistan and South Korea, and for two elements in Afghanistan and Vietnam.” The Philippines, which had ranked in the Top 10 countries for all three elements in 2015, had the most precipitous drop, ranking no higher than the 70th position in the 2019 study. There is a strong public reason for that unusual change of mind in their citizenry. In November 2017, after having vaccinated thousands of its citizens with Dengvaxia—a new vaccine against Dengue form the Sanofi company—the Philippines received a notification from the company that all the vaccinated individuals not previously exposed to the disease might have serious side effects after injection. The Philippine society reacted with extreme outrage and the government officials, who had hastily approved its purchase, were openly shamed by a body politic that suddenly lost confidence in vaccines.

The researchers found that being male and having fewer years of formal education were significant determinants of respondents’ aversion for vaccines; on the other hand women, who usually nurture the young children, are much more aware of the benefits of vaccines and the need to protect the safety of the society as a whole. Only in South Korea and Malaysia they found organized opposition and mobilization against vaccines, buttressed by mendacious disinformation campaigns in the web.

In a recent article in The New York Times, Denise Grady, Katherine Wu and Sharon LaFraniere said: “AstaZeneca revealed details of its large coronavirus vaccine trials, the third in a wave of disclosures by drug companies under pressure to be more transparent about how they are testing products that are the world’s best hope to end the pandemic. Polls are finding Americans increasingly wary of accepting a coronavirus vaccine. And scientists inside and outside the government are worried that regulators, pressured by the president for results before Election Day on November 3, might release an unproven or unsafe vaccine.”

In all political camps, there is a growing public mistrust against the authorities and the scientific community in general, after decades of disclosure of their misdeeds, real or imaginary, that have sapped the confidence of the common citizenry in them. Any clinical fiasco provoked by any major vaccine candidate against the SARS-CoV-2 will boycott its public acceptance and their eagerness to have it administered. If a large enough number of citizens refuse to be vaccinated, the herd immunity that we are all expecting in the next few months, will never materialize.

Now is the time to actively discuss the vaccine candidates and how to deploy them efficiently. 

Now is the time for regulatory agencies to inform what their guidelines for approval really are.

Stay distant. Stay safe. Stay beautiful.

What do you think? Please tell us.

Don’t leave me alone.

 

We need a vaccine with worthwhile efficacy

Recent new reports have exposed the subtle and not-so-subtle maneuvers of various governments to “bend the rules a little bit” in the process of certifying the efficacity and safety of the novel vaccines against the SARS-CoV-2 virus infection. Given that the vaccines, unlike the therapeutic products, will be administered to, not only people who are free of the disease, but also to individuals that are very vulnerable. After months of terrible suffering and thousands of deaths, Humankind cannot afford to make the mistake of using a vaccine that is either defective or not properly useful.

Three vaccine candidates – the ones designed by Pfizer, Moderna and Astra-Zeneca – are already well into the Phase 3 clinical trials, the last step before applying for regulatory approval by the Food and Drug Administration (FDA) and similar regulatory agencies. In a Washington Post article, Laurie McGinley and Carolyn Y. Johnson said: “A fierce debate has emerged whether the Food and Drug Administration should use its emergency authority to clear a coronavirus vaccine before it is formally approved – a move opponents warn could pose safety dangers and inflame anti-vaccination sentiment but others said could save thousands of lives by speeding protection from the virus.” On September 3rd the Centers for Disease Control and Prevention (CDC) warned the state health officials to start making preparations to distribute a coronavirus vaccine to health care workers and other high-priority groups by November 1st; that announcement immediately sparked a hot debate whether the Trump administration is actually trying to “push a vaccine” before the critical November 3rd general elections in the USA or not.

The vaccine(s) that will eventually be approved by the regulatory agencies must prove that, not only they show efficacity, but they will provide worthwhile efficacity. After the Phase 3 clinical trails show a certain degree of efficacity for a period of time, the vaccine candidates must be vetted for protection against severe forms of the disease and also enough long-term persistence of the protective effects by setting up double-blind placebo studies that might take many more months. Unfortunately, the world does not have the luxury of waiting 2,3, or even 4 years for this process.

In a comment to The Lancet Public Health, Philip Krause, Thomas R. Fleming and Ira Longini—members of the World Health Organization (WHO) Solidarity Vaccines Trial Expert Group—said: “There is a danger that political and economic pressures for the introduction of a COVID-19 vaccine could lead to widespread deployment of a vaccine that is in reality only weakly effective (eg. reducing COVID-19 incidence by only 10-20%) perhaps because a misleadingly promising result from an underpowered trial.” The massive deployment of a “weak vaccine” will have deleterious Public Health consequences for two major reasons:

  1. Authorities may wrongly assume that it represents the expected panacea and disburse major financial and human resources to deploy it.
  2. Vaccinated individuals may assume that they have the needed protection, disregarding the basic measures of protection like Social Distancing.

If the “weak vaccine” is compared to a worse under-performing candidate, we might have the bio-creep effect: the statistical programs might wrongly identify the “worse vaccine” as being non-inferior in the comparison. The WHO recommends that a successful vaccine candidate should reduce the risk of infection by at least half  and with a certainty that its true vaccine efficacity is at least 30%. The Food and Drug Administration (FDA) concurs with the basic threshold of 30% to show efficacy. “As an example of a result that would just satisfy these two criteria, an even randomized trial with 50 cases arising in those vaccinated and 100 cases in those given placebo would have a 95% CI that just excludes 30%, but would suggest 50% short-term efficacy.”

The authors argue that a global multi-vaccine trial with a shared control group might provide faster and more reliable results about their safety and efficacity. High enrollment rates of individuals for the clinical trials and the participation of many clinical centers worldwide might hasten the discovery and delivery of a candidate. Evaluation of safety in multi-vaccine trials might unmask certain adverse effects in some candidates that might not be present in the rest. One of the greatest risks for any vaccine is its potential to worsen the disease in certain groups, which might only be evident with a critically large number of participants over a larger period of time.

Spurious commercial and political interests have blocked the initiative of a multi-vaccine trial as the parties are keeping guard over “their” vaccines and are reluctant to share scientific and operational data with competitors and other governments. Sadly, Humankind has not yet succeeded in overcoming these pitiful petty interests.

Stay distant. Stay safe. Stay beautiful.

What do you think? Please tell us.

Don’t leave me alone.

The odds for vaccine gambling can turn awry

Some things in Life should never be rushed. Real love. Grilled meat. And vaccines.

In a New York Times article, Katherine J. Wu and Katie Thomas said today: “The pharmaceutical company AstraZeneca halted large, late-stage global trials of its coronavirus vaccine on Tuesday because of a serious suspected adverse reaction in a participant, the company said.” This report said that, according to some sources, that adverse reaction in one participant of the United Kingdom’s trial might have been transverse myelitis, a serious neurological inflammatory reaction to viruses.

The Oxford-AstraZeneca product is one of the most advanced vaccine candidates for the SARS-CoV-2 infection, with almost 30,000 participants in Phase 3 clinical trials around the globe. In a previous article, we discussed the encouraging early results of the Phase 1-2 clinical trials of this vaccine, which uses a viral vector to insert the SARS-CoV-2 genetic material into the human cells to provoke an inflammatory response. After assessing its efficacy, it is now being tested for its safety for humans, with extended Phase2/3 trials conducted in the United Kingdom and the Republic of India plus additional Phase 3 trials in Brazil, South Africa and 60 US testing sites.

The Oxford-AstraZeneca administrators did exactly what they were trained to do: once a major clinical complication arises, the whole process must be halted and the case (or cases) must be thoroughly studied by an institutional review board. That clinical complication could have been just a coincidence, but the possibility of a harmful side-effect must be carefully, patiently studied and vetted out. Moreover, large segments of the public in modern nations are already skeptical of vaccines; the emergence of a grave complication, like it happened with an early Polio vaccine in the 1950s, could drastically undermine the trust in this candidate, and others as well.

Aware of the above mentioned profound public suspicion about the safety of any vaccine candidates, nine pharmaceutical companies that are developing them recently signed a formal pledge not to seek any regulatory approval before all the necessary clinical trials have been completed and the data duly examined by them.

This is a welcome backstop to the various political pressures exerted, openly and surreptitiously, on pharmaceutical companies to rush a candidate to market to pander to the scared electorate. We should only pay heed to the “scientific date” for the vaccine’s arrival and not it’s “political one.”Governments that advanced many millions of dollars to speed the development and production of a good vaccine, must realize that they were in fact using “our money” for it.

Crossing fingers, they cannot cavalierly gamble our Health at the roulette table of Blind Hope.

Stay distant. Stay safe. Stay beautiful.

What do you think? Please tell us.

Don’t leave me alone.

Latest peer-reviewed data about the Novavax vaccine

Most of Humankind is hoping to be relieved from the terrible Coronavirus pandemic by the arrival of one (and preferably two) vaccines for the SARS-CoV-2 virus that has spawned it. However, the recent reports that there might be political pressures of all stripes to accelerate its arrival, maybe sidestepping all the traditional scientific procedures to certify it, as not only safe but also effective, has frayed the nerves of the concerned public opinion across the globe. Therefore if new and reliable data starts to appear about the more-advanced vaccine candidates, the scientific certification and public support needed for their regulatory approval will solidify.

In a previous article, we have already discussed the innovative design of the Novavax vaccine. C.Keech et al., from Novavax, have submitted a peer-reviewed article about the Phase 1 and 2 trials of their Recombinant Spike Protein Nanoparticle vaccine. They had set up “a randomized, placebo-controlled, phase 1-2 trial to evaluate the safety and immunogenicity of the rSARS-CoV-2 vaccine (in 5-ug and 25-ug doses, with or without Matrix-M1 adjuvant, and with observers unaware of trial-group assignments) in 131 healthy adults)” The participants were divided thus:

  1. a) Eighty-three (83) participants were given the vaccine plus the adjuvant.
  2. b) Twenty-five (25) participants were given the vaccine without the adjuvant.
  3. c) Twenty-three (23) participants received a placebo.

The researchers reported the initial results of the Phase 1, which was started in May. The Novavax vaccine is a recombinant nanoparticle vaccine designed with the full-length wild-type SARS-C0V-2 spike glycoprotein previously biologically primed in the baculovirus Spodoptera frugiperda insect cell-expression system. The rSARS-CoV-2 is resistant to the degradation to proteolytic cleavage, successfully binds with the hACEe receptor and is sufficiently stable at different temperatures. The company also manufactured the Matrix-m1, a saponin-based adjuvant, which was mixed with rSARS-CoV-2 right before the application to individuals. There were two injections in the deltoid muscle (both for the vaccine and the placebo) separated by 21 days.

First of all we must say that there were no serious adverse events for any  participants (thank you God Almighty for illuminating those brave scientists’ minds and hands) The addition of the adjuvant boosted the immunogenicity response by inducing a T helper 1 (Th1) response, which bode very well for the possibility of a much longer immunological defense for vaccinated individuals. Every participant was duly observed for half an hour after each injection and were given a dairy to carry home. “Predefined local (injection site) reactogenicity included pain, tenderness, erythema, and swelling; systemic reactogenicity included fever, nausea or vomiting, headache, fatigue, malaise, myalgia, and arthralgia.” The reactogenicity was also mild after the second vaccination and there was not a safety pause for any participating individual. The laboratory abnormalities of grade 2 or higher occurred in 13 participants (10% of the group) but were not associated with any grave clinical presentation. Six individuals (5 women and 1 man) had transitory lowering of the Hemoglobin values, with no evidence of microcytic anemia or hemolysis (destruction of red blood cells)

The evidence of an immunological defense set up by the bodies of participants was assessed by measuring the anti-spike IgG ELISA unit responses to rSARS-CoV-2 protein antigens, measured at days 0, 7,21,28 and 35. Those results were compared with a control panel of 32 (IgG) and 29 (MN) convalescent serum harvested form patients with PCR-confirmed infection that eventually successfully recovered. “ELISA anti-spike IgG geometric main ELISA units (GMEUs) ranged from 106 to 116 at day 0. By day 21, responses had occurred for all adjuvanted regimens…and geometric mean fold rises (GMFRs) exceeded those induced without adjuvant by a factor of at least 10. Within 7 days after the second vaccination with adjuvant…had further increased by a factor of 8…over responses seen with the first vaccination, and within 14 days (day 35) responses had more than doubled yet again, achieving GMFRs that were approximately 100 times greater than those observed with rSARS-CoV-2 alone.”

These initial results are certainly encouraging for those of us anxiously waiting for the vaccine.

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What do you think? Please tell us.

Don’t leave me alone.

Good news about the Novavax vaccine for the SARS-CoV-2 virus

In the mad dash of several pharmaceutical and biotechnology companies to create and test a good vaccine for the SARS-CoV-2 there might a “dark horse” in the crowded race. The company Novavax, that had already received a 1.6 Billion U$ grant from the American government to develop a coronavirus vaccine, have announced good results on August 4. Carl Zimmer and Katie Thomas report in a NY Times article that: “In one study, 56 volunteers produced a high level of antibodies against the virus without any dangerous side effects. In the other, researchers found that the vaccine strongly protected monkeys from coronavirus infections.” These results are being submitted in article proposals to peer-reviewed publications at the present time.

The 33-year company—that never made a commercially viable vaccine so far—used two techniques that are different form the ones we have already discussed. They are:

  1. They use a coronavirus protein that can elicit an immune response in humans.
  2. They use moth cells as more fast factories for a virus protein dubbed as spike.

In order to potentiate the effectiveness of the “spike” they added an adjuvant to the mix; data on mice studies had already established the value of using this adjuvant. They gave different combinations of the spike and the adjuvant to monkeys, who eventually developed good immunogenicity against the coronavirus, even erasing any traces of the virus in the respiratory or ventilatory systems in some of them. In  a Phase 1 clinical trial with 134 volunteers done last May, there were no side effects. After completing that initial trial, the researchers took serum from the vaccinated participants and mixed it with coronavirus and cells. They found a markedly protective effect in the serum that blocked the virus from infecting other virgin cells. They claimed that their vaccine finally produced more antibodies in the participants than in convalescent patients form a Covid-19 infection.

John P. Moore and P.J. Klassse reviewed in an article the prospective SARS-CoV-2 vaccine candidates and concluded that: “By far the most immunogenic vaccine candidates for antibody responses are recombinant proteins, which are not included in the ‘Warp Speed’ immunogens.” In the NY Times article, Dr, Moore was quoted as saying: “the strong response to the vaccine does not surprise me in the slightest.” The protein-based vaccines have a much longer track record of effectiveness than the novel viral genes-based vaccines, being licensed for Hepatitis B and Shingles. Three other protein based-vaccines—from Clover pharmaceuticals, the University of Queensland and Vaxine—are in Phase 1 trials. The US administration has granted 2.2 billion U$ to a joint project by the Sanofi and GlaxoSmithKline companies.

Stay distant. Stay safe. Stay beautiful.

What do you think? Please tell us.

Don’t leave me alone.

 

Good news about the Oxford-AstraZeneca vaccine for the SARS-CoV-2 virus

British scientists at the NIHR Oxford Biomedical Research Centre had previously used the glycoprotein spike on the surface of coronavirus—which allows them to anchor at a target cell—to produce a chimpanzee adenovirus—vectored vaccine against the Middle East respiratory syndrome coronavirus (MERS-CoV) They had called it ChAdOx1 MERS and represented many hours of study, research and hard laboratory work that would have hardly ever been funded by a private company—often only myopically seeking quick profits in detriment of the larger public good. When the Chinese authorities published the genome of the SARS-CoV-2, the Oxford scientists immediately started working on their template with messenger RNA.

The Oxford team partnered with other institutions in the United Kingdom and eventually got financial support from Astra Zeneca, a Big Pharma conglomerate. The ChAdOx1 nCoV-19 vaccine uses a replication-deficient simian adenovirus vector ChAdOx1 that contains the full-length structural surface glycoprotein of SARS-CoV-2 with a tissue plasminogen activator leader sequence. They had observed that one single dose of that vaccine had induced good humoral and cellular immune responses in monkeys; after high-dose vaccine challenges, there was a notable protection against the lower respiratory infection, a hallmark of the disease. They set up a combined phase 1 and 2 single-blind, randomized controlled trial, comparing it with a Meningococcal group A,C, W-135 and Y conjugate vaccine.

They recruited healthy adult participants aged 18-45 years old, excluding all those volunteers that had positive COVID-19 tests, had symptoms of acute respiratory distress, or were exposed to the disease like health care workers or first responders. The participants were randomly assigned to receive either the ChAdOx1 nCoV-19 vaccine or the meningococcal vaccine—they used an active vaccine because the lack of symptoms from normal saline injections could eventually “unblind” the controls. The participants were divided into four major groups:

  1. Group I: they had intensive early follow-up visits the vaccine’s safety and immunogenicity.
  2. Group II: they had higher blood volumes of humoral and cellular immunogenicity assessment than group 4.
  3. Group III: it consisted of only 10 participants that received a booster shot 28 days after the first injection.
  4. Group IV: participants that had a serum sample drawn for humoral immunology assessments only.

The median age of participants was 35 years old, 49.8% (536) were female and 50.2% (541) were male; the majority (9 or 90.9%) were white. Some received prophylactic paracetamol and some others did not; 328 (67%) of participants in the vaccine group and 180 (38%) of participants in the control group reported pain after the injection. The most reported systemic reactions were fatigue and headache. “In the ChAdOx1 nCoV-19 group, antibodies against SARS-CoV-2 spike protein peaked by day 28 (median 157 ELISA units EU) and remained elevated to day 56 (119 EU) in participants who received only one dose, and increased to a median of 639 EU (360-792) at day 56 in the ten participants that received a booster dose)”

Researchers concluded that one single dose of the ChAdOx1 nCoV-19 was safe and well tolerated, without any major reactions. A single dose of it produced an increase in the spike-specific antibodies by day 28 and the neutralizing antibodies in all the participants after a booster dose. Some studies showed that neutralizing antibodies in the dawn of the disease protected the rhesus macaque monkeys. Antibodies capable of neutralizing live SARS-CoV-2 were induced by day 28 and after a booster dose. T-Cell responses—considered essential for the ultimate defeat of the virus—were evident by day 7 after the dosage and peaked at Day 14. However, the booster dosages did not elicit a similar immunological response.

The researchers admitted that this study had serious limitations, foremost of all that it involved all healthy individuals that were not fully representative of their society. They designed Phase 2 and 3 trials that include older individuals and those at high risk of infection for the efficacy, safety, and immunogenicity of ChAdOx1 NCoV-19 given at a single or two-dosages in the United Kingdom, Brazil, and South Africa. Once they have enough data with adults, they will set up a study with children too.

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Does the BCG vaccination protect against Covid-19?

The incidence and mortality rates of the COVID-19 infections vary widely across the countries, depending on their availability of human and material resources, level of Public Health preparedness and the authorities’ local and national responses. Also there might be differences in ethnic composition, dietary habits, climate differences, social determinants, genetic material, and civic institutions to consider. One of the latest influencing factors that caught the scientific attention is the degree of anti-tuberculosis immunization of the population with the BCG vaccine.

The Bacille Calmette—Guérin vaccine was prepared with a Mycobacterium bovis strain of the TB producing organism in the famous Institut Pasteur of Paris in 1921. Since then several variants have been produced in the developed and developing world. Those of us not born in the USA, still harbor the memory of the painful injection given in our primary school years that left a little scar on our right shoulder. The initial strain was distributed to several laboratories of the world and six major variants were produced: Pasteur 1173 P2, Danish 1331, Glaxo 1077, Tokyo 172-1, Russia BCG.I and Moreau RDJ. At present almost 100 million children are still been vaccinated worldwide; as the vaccine provides little immunity for adult pulmonary tuberculosis, it has been largely discontinued in most fairly developed countries.

The examples of Spain and Portugal are relevant for the vaccine’s importance. Spain, which never adopted the BCG vaccination nationwide, has a mortality rate of 336 people per million inhabitants. Portugal—a neighboring country that shares many of the Spanish societal and cultural features—adopted the BCG vaccination in 1965 and only has a mortality rate of 56 people per million inhabitants.

Abhibhav Shama et al., mathematical researchers from the School of Computer and System Sciences of Jawaharlal Nehru University of New Delhi, studied the COVID-19 data from countries that had either had vaccination or discontinued schedules or never had any vaccination. They said that: “disease incidence and morbidity are reduced in countries with universal BCG immunization compared with those that have not adopted the vaccine. The finding also applies to countries in which variables such as climate, dietary habits, and genetic origin essentially coincide.”

During its long utility, the BCG vaccine has shown protective benefits for patients with other diseases associated with mycobacteria like Leprosy. Being a strong immunomodulator, it has been used to treat bladder cancer and other neoplasias.

The researchers divided their morbidity results according to the BCG penetration:

  1. Countries without a universal BCG policy (Belgium, Italy, the United States and the Netherlands) have an increased incidence of 9 +- 497.1.
  2. Countries with an ongoing BCG policy have an incidence of 9+-155.6.
  3. Countries that discontinued the BCG policy have an intermediate value of67 +-509.89.

The mortality results were divided as follows:

  1. Countries with an active BCG policy have 4 +- deaths per million people.
  2. Countries that discontinued the BCG policy have 5+- 33.6 deaths per mil.
  3. Countries with no BCG policy had 1 +- 56.8 deaths per million people.

Considering that the COVID.19 infection affects the older individuals more than the younger ones, the researchers studied its incidence among different age groups. They found that: “The results indicate three significant features as follows: (i) the disease incidence is very low for subjects less than 15 years of age and does not show significant dependence on the presence or absence of universal BCG vaccination policies. (II) The number of infected cases across the age groups is always higher for countries without universal BCG vaccination policy. (III) The differences between countries with universal BCG vaccine policy and countries without such a policy increase and reach their peak for age groups 45-64 and 65-79 years old.”

The researchers found significant differences in countries that had used different variants of the vaccine or combinations of them. The Brazilian and Russian variants of the BCG vaccine were not deemed to work effectively against the coronavirus; in contrast the Australian variant of the vaccine seemed to confer more protection.

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