Just a good vaccine will not magically fix the pandemic

Today, December 10th, an experts’ commission on vaccines from the Food and Drug administration (FDA) is reviewing the scientific data of the Pfizer-BioNtech vaccine candidate to eventually determine whether it is safe and effective against the COV-Sars 2 virus that has been producing this terrible pandemic we have been suffering for almost a year. As expected, we are all very hopeful that they will approve it.

In a recent paper in Health Affairs, A. David Paltiel—nominated by President-elect Joe Biden to join a group of experts to advise him on the pandemic’ cure—et al. warn us that there are other factors that will determine the vaccines’ effectiveness. They said that: “Using a mathematical simulation of vaccination, we find that factors related to implementation will contribute more to the success of vaccination programs than a vaccine’s efficacy as determined in clinical trials. The benefits of a vaccine will decline substantially in the event of manufacturing or deployment delays, significant vaccine hesitancy, or greater epidemic severity.”

In a June 2020 paper, the FDA stated that there are two pillars of vaccine efficacy:

  1. Ability to cut the viral transmission. The capacity of the virus to jump from an infected person to a healthy one and provoke the disease.
  2. Disease-modifying effects. The capacity to slow the progression of the clinical symptoms and to hasten the recovery process to save scant resources.

A good vaccine will have direct effects—preventing the spread of the virus—and indirect effects—reducing the infectivity of affected individuals. The FDA determined that there should be a transmission endpoint and a disease-modification endpoint. “Regardless of how a manufacturer defined their efficacy endpoint, the FDA also established a minimum efficacy threshold, specifying a primary efficacy endpoint point estimate of at least 50% to ensure—in FDA’s view—that a widely deployed COVID-19 vaccine is effective.” The determination of that relatively low efficacy—common in vaccines against influenza, a much less contagious and deadly disease—baffled many scientists, used to much higher FDA demands for vaccines. However, the terrible human, social and economic consequences of this pandemic might have exerted a deciding influence on the experts, desperate for a good cure.

In order to rigorously evaluate the efficacy of a vaccine, the experts must not only determine their usefulness to cut the transmission of the virus but also its beneficial effects to stop the progression of the disease in already infected individuals. Moreover the vaccine efficacy against the virus is just one of many factors at play.

These authors used mathematical models because they “asked how vaccine-related changes in susceptibility to infection, progression of disease, and severity of illness might translate into population outcomes of interest such as cumulative infections, hospitalizations and deaths. We explored how those downstream outcomes might vary in the face of alternative operational assumptions (e.g. the pace of scale-up and the degree of public acceptance) and changes in the epidemiological context.” The researchers used three different scenarios, based on the Rt reproduction number:

  1. Rt of 1.5, which represents the strict adherence to preventive measures.
  2. Rt of 2.1, which represents greater risk due to the winter weather and greater indoor activity.
  3. Rt of 1.8, which represents a baseline.

The Rt is the ratio of the infected and the potential victim of transmission; an Rt of 2.I means that for each infected individual, he/she will infect two other individuals.

The researchers utilized the Susceptibility-Exposed-Infectious-Recovered (SEIR) model, which considers the disease progression as “a sequence of transitions among a finite number of health states (or compartments)” First they divided the “infected” compartment into four well defined sub-compartments like this:

  1. Asymptomatic
  2. Mild (outpatient)
  3. Severe (hospitalized)
  4. Critical (hospitalized in an ICU)

Second, they account for the vaccination by creating a parallel set of compartments:

  1. Susceptible unvaccinated
  2. Susceptible vaccinated
  3. Exposure
  4. Infection
  5. Recovery
  6. Death

They studied three types of vaccines:

  1. Preventive vaccine. It decreases the likelihood of infection in a healthy person
  2. Disease modifying vaccine. It improves the health outcomes in infected persons.
  3. Composite vaccine. It combines the attributes of both types of vaccines.

For both types of vaccines they set the efficacy rate at 50% for both components; they examined ranges of 25 to 75% in sensitivity analyses. The time needed to reach effectiveness were considered to be:

  1. Fourteen days for fast acting, single dose
  2. Thirty days in the base case in two-dose vaccines with partial immunity after the first dose.
  3. Forty-two days for a two dose-vaccine with no efficacy after the first dose.

The effectiveness of a vaccine deployment drive does not only depend on the quality of the product per se but also on two implementation variables: pace and coverage. The researchers said: “In a population of 100,000 and at a baseline Rt of 1.8, the model projects 61,112 infections and 2755 cumulative deaths over the course of 6 months without a vaccine. Introducing preventive, disease-modifying and composite vaccines at baseline efficacy levels would result in 42,583, 39,767 and 1,199 cumulative infections and 1,896, 1318 and 1199 cumulative deaths, respectively.”

They found that a 50% effective disease modifying vaccine would have a greater impact on hospital admissions, clinical morbidity, and mortality than a 50% effective preventive vaccine. The impact of both vaccines would be similar in the worst epidemics but the disease modifying vaccine would have a bigger benefit in less grave epidemics. The 50% effective composite vaccine would have the best impact.

The researchers found that the potential benefit of any vaccine is highly dependent on the number of circulating virus at the time of its introduction in a community. When the viral spread, measured by the Rt factor, is relatively low, a vaccine with relatively low efficacy—for example 25%—has greater benefits on the morbidity and mortality rates that a much effective vaccine—for example 75%—introduced when the viral spread is relatively high. Where a vaccine lands, has consequences.

This study buttresses the opinions of many health care experts who are warning the public at large that only an effective vaccination drive with a good product will not magically erase the human, social and economic consequences of the pandemic. We must still continue to use the Social Distancing guidelines for many months to come.

Note. On December 10, the experts’ panel of the FDA recommended the Pfizer BioNtech vaccine for human use. On December 14, the first American citizen, an Intensive Care nurse in a Long Island hospital, was the first patient to get vaccinated. On December 17, the FDA panel will review the results of the Moderna vaccine. Let’s pray for the best!

Stay distant. Stay safe. Stay beautiful.

What do you think? Please tell us.

Don’t leave me alone.

Emergency Use authorizations for Covid-19 vaccine candidates

We are all extremely tired of the devastating health, economic and psychological consequences of the Covid-19 pandemic produced by the SARS-CoV2 virus. For the past few months, several scientific groups have been actively working in the design and preparation of vaccine candidates that will be both safe and efficacious. Recently we got very auspicious news from the Pfizer-BioNtech vaccine we had already discussed in a previous article.

On November 19, an article in The New York Times informed us that: “the drug maker Pfizer announced on Monday that an early analysis of its coronavirus vaccine trial suggested the vaccine was robustly effective in preventing Covid-19…The company said that the analysis found that the vaccine was more than 90 percent effective in preventing the disease among trial volunteers who had no evidence of prior coronavirus infection. If the results hold up, that level of protection would put it on par with highly effective childhood vaccines such as measles.”

Buoyed by these highly encouraging results, the companies are already talking about getting an emergency approval with the corresponding regulatory authorities. We have already discussed in another article how the deep public distrust of vaccination could undermine the generalized acceptance and eventual efficacy of a vaccine to cut the transmission chain of the virus in public and private spaces. A big challenge.

Do we have any recent scientific experience about provisional authorizations? Yes. In a comment published in The Lancet, Maxwell J. Smith et al.—after discussing the dubious validity of the Russian and Chinese vaccines that have not met the stringent regulatory controls of the Phase III clinical trials—said: “So why have the actions of Russia and China drawn such criticism? And how can other national regulatory authorities ensure that future emergency use authorizations for Covid-19 vaccines are issued in a way that is scientifically and ethically sound? Experience for emergency use authorizations for investigational Ebola virus vaccines in Guinea and Democratic of the Congo (DRC) can elucidate key lessons that can guide ethical emergency use authorizations for Covid-19 vaccines.”

In 2016, the regulatory authorities of Guinea granted a temporary authorization for an expanded access to the recombinant vesicular stomatitis virus (rVsV) vaccine that expresses the glycoprotein of Zaire Ebola Virus (ZEBOV) which induced and immunogenic response in the affected patients. Using a World Health Organization (WHO) protocol for scientific research ethics, the vaccine was approved for the individuals exposed to the Ebola-infected patients in a national vaccination drive. In the beginning of 2017, two other Ebola vaccines that were in Phase III of clinical  trials, but that were not yet licensed, were also approved for expanded access. In 2019 the Food and Drug Administration (FDA) approved these vaccines and in 2020 the European Commission followed suit, approving their medical use.

The authors state that there are two major differences in the regulatory requirements for the emergency approval of the Ebola and Covid-19 vaccines. First of all, the emergency authorization of the Ebola vaccines was done in an extremely transparent way. “The 2013-2016 outbreaks of Ebola virus disease in West Africa prompted WHO to develop an Emergency Use Assessment and Listing (EUAL) procedure to expedite the availability of vaccines.” This was meant as a guiding manual to engage the public discussion with representative institutions, media influencers and the general public about the unavoidable trade-offs in times of extreme social danger. Would the Guinean public be willing to accept “a little bit certainty” regarding the safety parameters for the concrete possibility of accessing a life-saving tool for millions of them, including children?  These authors stated that: “it is unclear whether these Covid-19 vaccines meet WHO manufacturing quality norms and standards, including whether the benefits outweigh the foreseeable risks.”

The second key difference is the disgusting chauvinism that “has infected” the larger public discussion of the many vaccine candidates, with most developed nations with the critical capacity to conduct clinical trials and to mass manufacture the product, fighting to be “the first one” to get the product to their citizenry and insisting of having early access to a vaccine before giving it to other less endowed countries. This resembles a “war with other means” and History has taught us that the first casualty in any kind of war is always the same: Truth. This geopolitical tug of war will compromise the access of poor citizens to the vaccines, with risks for us all. Moreover, can we really trust any product if we suspect that there are dark political interests behind its emergency use authorization? Talk of fear of The Deep State

Stay distant. Stay safe. Stay beautiful.

What do you think? Please tell us.

Don’t leave me alone.

Signs of Feminine Infidelity for dummies

Since the posting of our previous article about Clandestine liaisons in pandemic times, we have received a few discrete yet forceful email messages from our readers with varying kinds of commentaries. One of the most surprising has been the request of a manly reader (yes, men do read our page too) to share signs of wifely infidelity. Bowing to his request, we are sharing an excerpt from our new book Emotional Frustration – the hushed plague. Please remember that we are just re-transmitting “what others have said”, and it is not necessarily our opinion (sic)

Men brag about their affairs, but women—much better at histrionics as they internalize the script lines to give the illusion of veracity—are truly perfidious. For men, the feminine infidelity can be puzzlingly cryptic. What are its telltale signs?

  1. Suddenly having her cellular phone out of the reach of her partner.
  2. Excessively worry about her personal appearance.
  3. Make plans with “friends” that are unknown to her partner.
  4. Being unusually emotional and happy.
  5. Arrive home late from work and being hard to reach.
  6. The irrepressible impulse to hide her feelings.
  7. Being sarcastic and indifferent in her formal relationship.
  8. Lack of interest in her partner and common activities.
  9. Flirting with other men (or women) that might be old friends.
  10. Loss of libido and disdain for her partner. [i]

The last feature might be the easiest one to conceal, as supposedly women might be less keen on sex than men are, for which the latter often miss the mark. Antoni Bolinches said that some shrewd women before being unfaithful might fabricate a false couple crisis—based on real tenets or not—in order to buffer their guilt complex after their misdeed.[ii] Men are not the only ones having fun.  Esther Perel, a psychotherapist and author, said that since the 1990s, the number of women who have cheated in their couples increased by 40%.[iii]

A nugget of wisdom. Your wife stopped nagging you. Did the storm pass?  Beware. It is the eye of the hurricane before its outer ring comes crashing. Didn’t you notice that she cares more about her waistline and started a new diet? Didn’t you notice that she has some furtive chats in a phone unavailable to you? Didn’t you notice that she has new, exciting friends that are unbeknownst to you? Didn’t you notice that she works until late and comes back home with a smile?  Didn’t you notice that she seems absent-minded and hums ballads all the time? Didn’t you notice that she looks at you with a mischievous glint in her eyes? Didn’t you notice that even the family dog looks at you in a funny way lately?

Men try to callously conceal their transgressions by hook or crook.

Like a reverse-Sherlock Holmes, women blow clues to the four winds.

Usually women engage in adultery, not because they have “an irresistible urge for sex” like we men do, but rather because there are emotional frustrations that have been sapping her strength. If you want to find out how to remedy these situations, you might have to buy our new book…

References

[i] “Bajo Sospecha. 10 errores que cometen las mujeres infieles (y las delatan frente a sus maridos)” Entemujeres, Clarín, Buenos Aires, 23 Enero 2015.

https://www.clarin.com/pareja/infidelidad-mujer-_infiel-engano-trampa-amantes-sitio-internet

[ii] “Vinculos” Ibidem as above.

[iii] Esther Perel “The State of Affairs: Rethinking Infidelity”, Harper Collins, New York, 2017.

Stay distant. Stay safe. Stay beautiful. 

What do you think? Please tell us.

Don’t leave me alone.

Clandestine liaisons in pandemic times

-“Doctor…Gave up all my social life, except my virtual dating – My daily dose of oxygen.”

Verónica X. is a successful lawyer with a stellar career in a competitive business realm who has a nice family that has backed her all along the expected ups and downs, including a supportive husband and two teenage daughters that admire her.  For all her personal and professional achievements, she still longs for the adrenaline shots she used to get in “her rather hectic days” as a college student in the 90s. She still keeps a roster of girlfriends from those times that meet with her once per year in order to remember their “wild times” and laugh all along a nice dinner outing.

However, what constituted an unexpected, and most welcome surprise, was the re-connection with an old flame that burned intensely for several months in her senior year. Due to the not-so-subtle pressure from the unwritten yet very influential rules of her starchy social milieu, she dumped him for “one of her own kind”, which she still resents in spite of her supposedly “perfect marriage.” Out of the blue, he found her in a Facebook page and send her an open invitation. Initially she considered dismissing him as a thing of the past, but she was curious. Extremely piqued.

In the beginning they were both skittish, talking inconsequentially about their old times and their present family structures, but slowly the talk became more erotic. After a several weeks-courtship in the web, they became de facto “spiritual lovers” again, openly dreaming about a future physical encounter. They are both professionals who, in spite of working largely at home during the pandemic, can still snatch some secluded time in their home offices for a chat almost anytime under the cloak of a pressing “business conference.” What used to be an escapade in the 9 to 5 regular working hours has shifted to the after-hours when the rest of the family is distracted with a Netflix series.

Feeling a little bit sated with the precious personal and professional objectives she had fought so hard to reach, Verónica X., like the central character in our novel, feels the irrepressible urge to shake her torpor and boredom. Hedonic adaptation is a psychological phenomenon whereby the initial excitement of a new situation, a new relationship, a new purchase, etc. slowly starts to wear down and we go back to our previous emotional state. Veronica was in the beginning very happy to take possession of a privileged social status that she would have never reached if she had married her former penniless boyfriend. But over the years, the joy of having a nice mansion in the suburbs, three cars in the driveway, spare money to splurge on shopping, eating out, vacations overseas, etc., all that begun to lose its initial shining and looked aged compared to the possibility of feeling a romantic thrill again.

As related by an article published on October 24 in Clarín, an Argentine newspaper, “a survey done in the site for the unfaithful called Second Love (they actually used the English term), 80% of the 989 participants confessed that the quarantine increased their desire to meet other people outside their stable relationship. But, at the same time, only 10% has materialized a date from the time the pandemic was declared (from a total number of 1102 cases)” The majority of respondents claim that they have maintained the rules of Social Distancing during their clandestine encounters. Only 36% of the respondents admitted using the videoconferencing to have some intimate moments with their paramours; paradoxically 32% of the respondents admit that their partners do know about their use of the social media.

Walter Ghedin, a psychiatrist and sex therapist in Buenos Aires, said: “the fantasy of an affair has surely come up some long time ago and it has most likely stalled as a mental elucubration without ever translating into an act…The ever enduring cloistering due to the pandemic has affected the sexual desire, especially in the couples that share the same residence…In fact those that are daring to try a tryst in the context of a pandemic might consider it as an excitatory stimulus that they cannot find in other activities.”

The predictable, safe alternative might not excite us erotically. But the mysterious stranger will make us dream.

Stay distant. Stay safe. Stay beautiful.

Note – The featured reproduction of Gustave Courbet’s Amants was taken from Wikimedia Commons. https://commons.wikimedia.org/wiki/File:Courbet-Amants-Lyon.jpg

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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.

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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.”

Stay distant. Stay safe. Stay beautiful.

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.