When I first started this academic blog, COVID-19 had already ravished millions of victims worldwide. It became the new headlines of newspapers worldwide. Quarantine and vaccine became the new buzzwords of the day. Commentators and politicians were obsessed with the idea of the new vaccines. Daily press conferences from Downing Street disseminated information that appeared more dismal as days passed. It was unfathomable to the ordinary person that life would get easier as the year 2020 comes to an end. Fear not, as in the recent few weeks, we've got the results coming back from analyses of major vaccine trials. The major candidates are undoubtedly the Oxford-AstraZenca enterprise, Moderna and Pfizer. Only the Oxford COVID Vaccine published, on The Lancet, the results of the interim analysis of its Phase 3 Trial executed in the UK, Brazil and South Africa. [1]
Figures over 90 per cent reverberated in news reports, sparking hope and optimism in dismal communities that just require that joyful tint for Christmas and the holiday season. However much of a kill-joy I might come across, I do have to confess I have been sceptical about these figures all along. I liken it to a bid - 90, 95, 97...One has to acknowledge the fact that figures are subjected to statistical manipulation and in an era where an urgent health solution is required, there are no qualms in the extent of manipulation executed in order to maximise financial gain and acquire public and political support. I have arrived at the stage when I don't even trust news reports anymore. This is not a mere whim tantamount to that of a somewhat deranged, orange-skinned adult baby who would not concede amidst an election defeat (we all know who that is) - instead, it is the conclusion I regretfully arrive to after months of witnessing how major news outlets manipulate the public mood and create bouts of fear and apprehension across cross-sections of communities. Major avenues of the mass media who pander to populism instead of portraying both the good and the ugly.
The Guardian's recent article [2] on the Oxford COVID Vaccine has revealed the disparities in vaccine efficacy between early group and main group analyses (we'll come back to this later). Nonetheless, it exposed an overwhelming sense of optimism that blighted its view when it comes to adverse events and long-standing issues of immunogenicity. It also lauded the vaccine as the mainstay of the UK's vaccination programme and allayed fears over durability by citing one of the researchers saying: 'we shouldn't get too hung up on comparing these early numbers.' One might think such words have fully addressed the durability concern. However, this quote came shortly after the claim that the Oxford vaccine technology (more on that later) was meant to invoke a long-term immune response. By adding the quote, it exhibits an overwhelming level of arrogance. Translating it to emotionally rawer terms - 'We have got this covered. Even though some of the results don't look right now, they will in the long-term and our vaccine is, by default, durable.' This is not helped by the praises by the volunteers of the Oxford trial echoing the chambers, duly captured by another article published by The Guardian. [3] That piece erred drastically in lacking any sort of scientific rigour - a piece devoid of merit, painting nothing but an unrealistic image of what the vaccine is expected to bring. It is unthinkable how reporting the reactions of trial volunteers only is going to contribute to the overall, constructive conversation about whether the vaccine is going to work in real life.
The news article published by Sky News [4] is even worse. It has not even addressed the major issues arising from the analysis. It resorted to mere citing of what a professor of the trial had said about the trial, which is, frankly speaking, the worst person one could have ever cited when it comes to scientific trials since it is highly unlikely that a member of the team would be critical towards the project. No controversial views were proffered. The disparity in vaccine efficacy (to be elaborated below) is only glossed over. The inability of major news outlets in exposing the shortcomings of the trial is alarming, considering their role is to hold major public operations to account in the name of public interest.
Chest X-Ray (AP View - Erect; done in emergency settings) - showing COVID-19 pneumonia changes. What can be immediately appreciated are the vast bilateral areas of opacity. Such consolidation is particularly concentrated over the upper lobes of both lungs, though the apices are less affected. There is no pleural effusion - the costophrenic angles are clear. There are also multiple air bronchograms observable. The heart is enlarged (though I would actually measure it were I given a tape; I mean the cardiothoracic ratio) and the mediastinum is widened (most likely due to mediastinal lymph node enlargement). This diagram is extracted from: https://images.squarespace-cdn.com/content/v1/546e1217e4b093626abfbae7/1583509666801-3MYG1DWJG8QUKOEN21E7/ke17ZwdGBToddI8pDm48kJgA3QZvk05htwH_OrPEISx7gQa3H78H3Y0txjaiv_0fDoOvxcdMmMKkDsyUqMSsMWxHk725yiiHCCLfrh8O1z5QHyNOqBUUEtDDsRWrJLTmaJA7qX762m5M2zpZbiZXpaOUvNBQk8Agr67GS2BV7qjy-NgV75LamRYYIUJprjWC/Portable+CXR+%28COVID-19%29.png.
My scepticism might be, in itself, a huge problem and criticised as an attempt to undermine the efforts of scientists working around the globe to achieve something. My diatribe can, at the same time, be construed as the words of a person at leisure, typing away on the keyboard in reckless disregard to the lives lost during the COVID pandemic and the urgent need for a vaccine. My acrimonious prose can be held as evidence against me, that I am no more than a non-contributing coward. The truth is, I can be all of those things. However, vaccine trials do not equate success. We live in a world of science. Science is about trial and error - never giving up. It doesn't matter if we've got it wrong the first time. What truly matters is being praised by populist politics and not knowing when one is right or wrong. Being lauded is naturally a thing to relish, but the ensuing arrogance also drives one to blatant ignorance towards the flaws of one's project, until serious consequences break out. That's why we have peer reviews. That's why we have expert committees to scrutinise trials. Scientific rigour and a healthy dose of scepticism are conducive to success in the long-run. Without feedback and constructive criticism, one could never improve. Earlier this year, the Surgisphere scandal led to the retraction of a study which purported to show the increased rates of mortality associated with the administration of hydroxychloroquine, a drug touted by Donald Trump as a 'wonder drug'. [5] Hydroxychloroquine, at that time deemed as a key drug for the treatment of COVID-19, received much public hype. This is when peer review and scientific scrutiny, as well as critical feedback, are of paramount importance. Due to errors in the peer review process, nobody was able to identify the obvious - Surgisphere was a hoax. The data extracted from this 'purportedly accurate' source turned out to be inaccurate. Science is fundamentally different from the arts and humanities in this respect - we seek the truth through evidence. We don't discuss opinions, let alone imaginative ones, without concrete facts and data.
The interim analysis of the Phase 3 trial of the Oxford COVID Vaccine was published online two days ago. I read it today from top to bottom and identified some glaring errors and inconsistencies. It might have reported an efficacy rate of 90 per cent. Zooming in to the methodology though, one would not be subjected to too much difficulty to see what is wrong with it. If it certainly is the 'most important vaccine globally' claimed by the Guardian, I hope it is subjected to more scrutiny than it currently receives. Concerns must be addressed promptly.
The Paper [1]
The analysis pools data from trials performed in the UK, South Africa and Brazil. There are four trials in total - COV001 (UK), COV002 (UK), COV003 (Brazil) and COV005 (South Africa).
What the vaccine is trying to achieve: I think it is necessary for me, before I proceed, to clarify what a vaccine is actually used for. This may sound condescending, but I am sick and tired of people in the media claiming, without any scientific foundation, that the vaccine is a panacea saving those who catch COVID-19. This just in, it doesn't. On the contrary, it puts COVID in the body. This is not exactly true, with regard to the Oxford COVID Vaccine. The vaccine contains a sample of the virus (in the broadest sense). It is intended to be totally harmless and the crux of injecting such viral material is to stimulate the body's immune response. It is a well-known fact that the immune system is only truly 'turned on' upon its second contact with the microbe. This is also why vaccination is not available to those with impaired immunity, such as diabetes mellitus and HIV. Those patients benefit from what we call 'serum transfusion', in which the serum of those who have recovered from a virally-induced disease is extracted and transfused to these patients, so that the antibodies generated by these recovered individuals can be used to help those who can't generate their own. Thus, to summarise, vaccines are not drugs - they are merely stimulants of one's immunity. A fire drill, so that when the vaccinated individual does encounter the microbe in the wild, the immune system knows how to respond in a more robust manner, resulting in better health outcomes.
Diagram showing T Cell Activation (Extracted from: http://1.bp.blogspot.com/-D_hbhlapt04/UfA07KK9zAI/AAAAAAAAAcU/0Yzcm92Fw9s/s1600/49_14_T_cell_activation-L.jpg)
What the Oxford COVID Vaccine contains: Adenoviral vector containing the gene for the SARS-CoV-2 structural surface glycoprotein antigen.
This is very likely, to most people, to be a bundle of words that carry no meaning. Well, that's where things get quite complicated. I've previously talked about putting viral material into the body to elicit a reaction. That is the overarching principle. Throughout history, loads of different methods have been adopted for making vaccines. Some of them are inactivated, where the entire microbe is being 'switched off' and injected into the body. A prominent example is the oral polio vaccine, which has successfully led to the eradication of types 2 and 3 polio (Type 1 polio is still wandering in the woods**). [6] These 'switched-off' microbes (can be viruses, bacteria and so on) cannot, theoretically, cause any havoc while it's in the body. However, due to the presence of antigens on the microbial surface, the proteins betraying their identity, the immune system picks up the antigenic signals. Such recognition triggers a series of immunological processes. Next time, when the virus really attacks the individual, the immune system, like a mobilised army, can fight the virus off effectively.
Apart from inactivation, there is 'attenuation'. The literal meaning of the word can be adopted to understand more about this technique. We go for a severely weakened form of the microbe and inject it into the body. Bear in mind that it is generally safe, if not entirely, to do so. The microbe can be likened to an old man incapable of even fending for himself, let alone ravishing other cells. A prominent example is the BCG Vaccine for Tuberculosis (TB) [7], It is not available in the UK's routine vaccination programme provided by the NHS [8], due to the relatively low incidence of TB in the country. The funny thing about this vaccine is that it doesn't use the microbe which causes TB (Mycobacterium tuberculosis). It uses a poor relation of it, Mycobacterium bovis, which is highly attenuated when prepared into a vaccine. In developing countries where clean, drinking water is more of a luxury than the norm, Mycobacterium bovis can cause intestinal TB.
These methods of making vaccines are pretty standard. However, to understand the Oxford way of making the COVID Vaccine, we first need to know what a vector is.
Illustration of how a viral vector works, extracted from: https://s3-us-west-2.amazonaws.com/courses-images/wp-content/uploads/sites/1094/2016/11/03164948/OSC_Microbio_12_01_GeneTher.jpg.
As we can see in the diagram above, a vector can be anything. It can be a virus, in this case: an adenovirus. It simply means a genetic transmission device. The viral DNA in the above diagram is modified so as to contain BOTH viral and target DNA. By target DNA, I mean the DNA that helps us synthesise a protein that we want. It can be any protein, depending on the gene. Viruses are good at injecting their genetic material into cells for reproduction. They are thus known as non-living when not having a host, since the only time they exhibit the characteristics of living things is when they attach to somebody and launch an unadulterated assault. The genetic material of the virus enters the cytoplasm of the cell. When the time is right (as I explained in the previous articles, viruses only attack when the time is right. The rest of the time, the genetic material becomes an enclosed entity called an 'episome', where it is inactive and does not replicate), the viral genetic material combines with the material of the host cell. This jumbled-up DNA then becomes important for the manufacturing of proteins. Remember, the nucleus of the cell is the starting point for protein synthesis of the cell. It kicks off a process called transcription. For more details, refer to the diagram below.
Diagram showing the processes of protein synthesis (extracted from: https://i0.wp.com/astarbiology.com/wp-content/uploads/2017/01/02.jpg?resize=1360%2C1145)
We get what we want. The target gene gets synthesised, with the bounty of resources within the cell, into the lovely protein that we desire.
Unpacking the chunky term describing the contents of the Oxford COVID Vaccine using this basic principle, we seem to have got our answer. An adenoviral vector - using an adenovirus as a genetic carrier - carrying a specific gene (our target DNA or gene) which will one day be manufactured, by our body cells, into an identity badge of SARS-CoV-2 (the virus causing COVID-19). The identity badge is the antigen of the spike protein on the viral surface, the one required for one's immune system to recognise and mobilise the forces before the real event kicks in.
This also reaffirms the point I've made earlier. A vaccine is not a panacea. Far from it, it's tantamount to throwing you to the deep end. You are given a sample of the virus (or an identity badge of it, rather than the entire entity) and your immune system is responsible for recognising and dealing with it. The identity badge triggers the mobilisation of forces, readying oneself for war. It's not the vaccine that cures you, but yourself. That's why what Boris Johnson says regarding the vaccine, however eloquently put, is utter nonsense. The 'searchlights of science' does NOT give us the power to 'stop that enemy from making us ill'. The vaccine also does NOT act as a 'biological jiu-jitsu' which 'turn[s] the virus on itself'. [9] In fact, it does the opposite - it makes us sick (not ill - I know it is rather pedantic of me to pick on individual words used in one's speech, but the word 'illness' is more related to the subjective experiences of the patient). It is our immune system that ultimately saves us.
Primary Outcome of Study: Virologically confirmed, symptomatic COVID-19 (defined as NAAT-positive swab, with at least one qualifying symptom, such as fever => 37.8 C, shortness of breath, anosmia, or ageusia);
Two Main Groups: COVID-19 Vaccine (Intervention), Meningococcal Vaccine (Control).
For clarificatory purposes, anosmia refers to the loss of smell. Ageusia is the loss of taste. Shortness of breath is to be understood by the ordinary meaning of the words and is a subjective experience. However, I would imagine that it will be accompanied by tachypnoea (increase in breathing rate to above the range of 12 to 20 breaths per minute) and is persistent rather than related to exertion or certain postures.
Substantive Issues:
Let us consider several issues associated with the study: (1) baseline characteristics of participants, (2) side effects, and (3) discordance in dosage and timing,.
This table is extracted from [1] and shows the baseline characteristics of the participants recruited in the study. Note that COV002 UK (LD/SD) and COV002 UK (SD/SD) are from the same trial. They are separated in the table due to the fact that different doses are administered. This is a point I'll come back to later in the analysis.
The first issue is Age and Demographic Subgroup: From the methodology, it is stressed that the original idea is to recruit healthy participants aged 18-55. Those with underlying health conditions are excluded in Phase 1 of the trial, whereby the results were reported earlier in the year. [10] In COV002, Phase 2/3 (trial), those working in healthcare settings (or more accurately, those in high occupational exposure to COVID-19) are recruited. The age range was originally restricted to 18 to 55 years. Enrolment of older participants began from 8 August, where all of them are given the standard dose regimen (SD/SD if you're referring to the table above; No participant aged over 55 is given the LD/SD regimen). This is a very serious issue. It is well-known that COVID-19 afflicts the elderly the most, especially those with underlying health conditions, where the mean age of incidence is 45 years, according to a Lancet study published in April. 61 per cent of the cohort (afflicted with COVID-19) are aged above 40 years old. [11] It is unknown, in virtue of reading this paper, why the study has decided to recruit mostly young and healthy participants without regard for the possibility of recruiting members of the older age groups. It is initially understandable - at the initial phases of the trial, one wants to test the efficacy and safety of a vaccine. The population is therefore healthy and standard, since the elderly are more susceptible to underlying medical conditions and such factors may be confounding. However, stepping into more advanced phases of the study, there is no sensible reason why the cohort cannot be more representative of the community. Is it legitimate and reasonable to derive that this vaccine is going to be equally effective in the elderly population just because it works well in the adult population, assuming there are no other technical flaws in its methodology?
In terms of gender, they're nearly evenly split. I don't think there's much problem here.
BMI - Body Mass Index: Obesity is a major risk factor of COVID-19 and is associated with poorer prognostic outcomes of disease. [12] This is associated with the decrease in adiponectin release, which can contribute to the derangement of a variety of metabolic processes. Moreover, fat can be stored in organs outside of fatty tissue - the liver, lungs and so forth. Fat storage in the lungs can lead to impaired ability of the patient to fight off the virus. Chest fat can also lead to laboured breathing - with impaired ventilation, it is harder to remove the virus from the lungs. It therefore accumulates and replicates. In this cohort, the average BMI is around 25-26, which is alarmingly normal by WHO Standards (discounting racial differences). It is not representative of those who are clinically obese. Although those with BMI > 40 are explicitly excluded from the trial [13], the homogeneity of the cohort remains an insuperable concern. Whether the results of this trial can be replicated for this subgroup of individuals is still unknown.
I have nothing against health and social care workers. Absolutely nothing, regarding that I am an aspiring member of the workforce. However, this is both alarming and worrying. One plausible reason for this worry is that this vaccine works and produces a robust immunological response because these workers have already been exposed to COVID. Many of which may be asymptomatic or have only displayed mild and non-specific symptoms. Especially at the early stage of the pandemic, COVID testing was not readily available. Many of which might already have developed antibodies against COVID by the time they're given the vaccine. The trial's failure of securing most participants from the community raises questions regarding the reproducibility of the data. Some may argue that according to clinical trial data stored in the US National Library of Medicine [13], the following categories of participants are excluded and any worry is ill-founded: (a) history of laboratory-confirmed COVID-19, (b) those who have been at high risk of exposure before enrolment, and (c) living in the same household as any vulnerable groups at risk of severe COVID-19 disease. This net is, however, not comprehensive enough. In fact, no net can ever be comprehensive enough to avoid confounding. The most feasible solution is to recruit more participants from the community. A less homogenous cohort works in the long-term since it provides us with a better glimpse of how the vaccine works in the broader community. In real-life, not merely in hospitals and care settings. Moreover, as I stated earlier, COVID testing was not readily available during the early phases of the pandemic. Supplies were in shortage (remember the PPE fiasco?) and everything was in a mess, in absence of a more refined word. There can be asymptomatic or mildly symptomatic cases of the disease that fall off the radar. We need a vaccine that speaks for the populace, not a mere stratum of it.
Update: 11 December 2020:
My argument against the sole recruitment of healthcare workers still stands. It has come to my attention that the Oxford COVID Trial also purported to exclude those who are seropositive before testing. However, we all know that seroconversion does not happen immediately. Seroconversion is the process whereby a microbe enters the body and wreaks havoc. The body then mobilises and produces antibodies to get rid of them. This process takes time and is not miraculous. According to a brief communication published on Nature Medicine Journal [17], the positive rate for IgM production (one of the antibodies indicative of infection in the short-term) is at 94.1 per cent approximately 20 to 22 days after symptom onset. That for IgG (an antibody indicative of infection in the long-term) is 100 per cent approximately 17 to 19 days after symptom onset. Although these periods might seem short to you, they mean a lot and constitute to a possible confounder in the analysis. It is very possible that an asymptomatic or mildly symptomatic (defined as those with mild, non-specific symptoms, not having received a COVID test - this is highly possible since many dismiss it as a cold or weather change) participants are recruited in the study and they are tested for seropositivity. However, at that point, the body is still in the process of viral clearance and has not produced an antibody level high enough for detection.
This brings me back to the idea I've reinforced through analysing the cohort data. Recruit participants from more sources so that the sample is more representative of real-life. Once the methodology is faulty, no matter how many exclusions you put, there will still be errors.
5. Ethnicity: This is nothing short of a disgrace. According to the table up there, over 90 per cent of participants are of white ethnicity. I am not expressing any political views on the matter, nor am I exhibiting any overt racial prejudice. The disgrace originates from the fact that the trial does not reflect the racial make-up of the United Kingdom. More importantly, it fails to take account of the fact that certain ethnicities are more prone to contracting COVID-19 and poorer clinical outcomes, such as admission to the ITU (intensive treatment unit). In a study published by The Lancet [14], individuals of black and Asian ethnicities are more prone to contracting COVID-19 than their white counterparts (risk ratios: 2.02 for black, and 1.50 for Asian) [main analysis]. Individuals of Asian ethnicity and mixed ethnicity are also subjected to higher risk of death and ITU admission (risk ratios respectively: 1.97 and 1.48). It is totally unthinkable that the Oxford COVID trial recruits mostly white individuals, as if the mere recruitment of white individuals can provide us with results reflective of a multicultural and multiethnic country such as the UK. Heed that the vaccine is going to be made available to the 'world'. Does this reinforce the arrogance that the world is dominated by white people whereas other ethnicities don't count? It is unknown whether racial differences contribute to differences in vaccine responses (immunological responses). And from this trial, we can never know.
6. The inclusion of diabetic patients to this study might be beneficial, if only the results garnered from this subgroup are analysed on their own. Diabetic patients, notwithstanding their glycaemic control (although this actually makes a significant difference), still have weaker immune systems as compared to the general population. Pooling their results to the main analysis might contribute to, however small, a difference. It has to be noted that performing a subgroup analysis dedicated to diabetics can tell us more about the efficacy of the vaccine in this stratum of the population, thereby identifying any serious adverse consequences which may be associated with diabetes itself.
It is acceptable and normal for healthy participants to be recruited for phase 1 and 2 trials since the overarching aims are to establish the correct dosage, timing of administration (interval between doses 1 and 2), efficacy of the vaccine and any relevant side effects (including severe adverse events). However, stepping into phase 3, it is deflating to see the Oxford COVID Vaccine Trial not being able to recruit patients with chronic medical conditions (well-controlled) like the Pfizer vaccine trial.
ECG showing Sinus Tachycardia (meaning that the heartbeat originates from the SA Node [normal] and the heart rate is higher than normal; here: 21 x 6 = 126 beats / minute, where the normal range is 60-100 beats / minute) - the most common arrhythmia associated with COVID-19 (extracted from: https://ddxof.com/wp-content/uploads/2018/02/ecg_5.png)
Side Effects:
[1]
There are 175 adverse events in total, where 84 have occurred in the COVID group and 91, the control (given the meningococcal vaccine). On face, it might appear that the COVID-19 group reports better outcomes. The paper stresses on the occurrence of transverse myelitis. Whether there are other types of adverse events remains unknown, according to the information published. Transverse myelitis have various aetiologies, including post-vaccination and viral infection. Over 73 per cent of cases involving vaccination have occurred within a month post-vaccination. Furthermore, 20 to 40 per cent of cases are attributable to viral causes. 46 per cent of patients have a preceding viral infection, pointing towards an immunological reaction subsequent to the infection rather than directly related to the infection itself (the immunological process is called molecular mimicry, where the immune system of the individual recognises body cell material similar to viral material and starts attacking self material). [15] There are three cases of transverse myelitis originally attributable to the COVID-19 vaccine, where 2 are excluded after consulting expert neurological opinion. 1 case of transverse myelitis pursuant to vaccination may seem anomalous, but it is not that simple. The authors have not elaborated on the circumstances of the patient in question. The development of transverse myelitis can be intrinsically related to an increased tendency of autoimmunity. This may imply that when this vaccine is released to the community, there might be an issue with patients who are sufferers of autoimmune disease. However, it doesn't end here. What about those with mild allergies or family history of allergies/autoimmune disorders? What about those currently under remission of systemic autoimmune issues such as lupus or scleroderma? More research has to be performed in this area in order for the vaccine to work for the majority, not the few.
For those interested in the full list of adverse events and their prevalence in the cohort, refer to [10]. It is unfathomable why they don't aggregate and present the adverse events from the four different trials (2 in the UK, 1 in South Africa, 1 in Brazil) in this paper [1]. I must have missed something if they did.
Discrepancies in Dosage and Timing:
[1]
This is perhaps the nail on the coffin. Originally I had no idea why they decided to have two subgroups: Lower Dose / Standard Dose(LD/SD) and Standard Dose/Standard Dose (SD/SD). Originally, I postulated that they might be experimenting with different regimens. It turns out that, as I scrutinise the section labelled 'Study design and participants', it is an ad hoc exercise. It was intended to be a one-dose regimen. However, as time passed, the immunogenicity was found to be higher with two doses. That's why they've added a booster dose.
There was an issue with the quantification methods used. The two methods were respectively quantitative PCR (or qPCR) and spectrophotometry. A dose of 5 x 10^10 viral particles (as measured by spectrophotometry) was adopted. It was equivalent to 2.2 x 10^11 viral particles as measured by the qPCR method. However, problems occurred with spectrophotometry, including the fact that a lower immunological reaction was detected by using that method. That's why they decided to switch to qPCR and increased the dose (as measured by qPCR) to 5 x 10^11 viral particles per vaccine. It is alright to make mistakes, especially in the realm of science. It is perfectly normal for us to be wrong sometimes. It does not matter. However, against the backdrop of humongous political pressure and attractive financial gains, the trial seemed to have gone against all its principles and decided to pool all results together. Citing the study:
'the regulatory authority acceptance of the inclusion of the two trial regimens (LD/SD and SD/SD) in analysis was based on the observation that these regimens generated similar levels of binding antibody, and would therefore increase the sample size available for analysis without compromising efficacy.' [1] (p. 10)
First, I don't think I should be able to comment on the issue of binding antibodies since this is merely a purported fact, backed up by virtually no evidence in this paper. Moreover, as we shift our attention to Table 2, we can see some glaring inconsistencies. Not knowing why they've decided to up the dose from 2.2 x 10^11 to 5 x 10^10 aside, the vaccine efficacies are very different between the LD/SD and SD/SD groups. They are respectively 90.0 per cent and 60.3 per cent in the UK cohort. The Brazilian cohort, with the SD/SD regimen administered, reports an efficacy of 64.2 per cent. The final figure of 70.4 per cent promulgated in news reports is the conflation of two entirely different cohorts subjected to entirely different regimens. Assuming that the original aim of increasing the dose of the vaccine is to maximise its efficiency, it has colossally failed.
Also, not being an absolute prude, there are variant intervals in the administration of the 1st and 2nd doses of the vaccine in Brazil and South Africa. While I appreciate it might be a logistic issue, the effects might be significant. In Brazil, the gap between the 1st and 2nd doses can be up to 12 weeks, although a target of 4 weeks is established. In South Africa, it is firmly established at 4 weeks. In the UK, due to the initial mistake, participants in older age groups are also subjected to shorter intervals in administration of the 1st and 2nd doses, whereas those in the 18-55 (years) age group, significantly longer. This is a logistical issue. The gap might seem to some as negligible- to me, such discrepancies might muddle the waters and take the results garnered from the trial to the realms of shaky science.
One general, extra point: It is also common knowledge that we need more time to decide whether a vaccine can protect us for long periods of time. A BCG Vaccine (as we've seen above, it's the one for TB) can confer protection for fifteen years. The MMR Vaccine (Measles, Mumps and Rubella) (provided that two doses are taken) confers life protection. [16] Due to the fact that these trials have only been initiated a couple of months back, with the entire COVID-19 issue having arisen in February, it is near-impossible to evaluate or project the long-term effects of the vaccine. That's why such interim analyses should only be regarded as a reflection of the present. More analyses have to be done in the future to monitor its efficacy in the long-run, as well as any possible adverse consequences (such as transverse myelitis, or any other manifestations of autoimmunity).
Conclusion:
I am quite appalled by this study, if I am being totally honest. I have started off being sceptical, but optimistic. A healthy dose of scepticism is conducive to scientific development. As scientists, we should never be complacent. Question everything and ask better questions as we become more competent. Answer them, bearing in mind that nothing beats scientific rigour. However, this trial is anything but rigorous. There are many issues arising from this trial, ranging from the demographic features of the participants, to the design of the study. Conflating the two subgroups, despite their being given different doses of vaccine, is the final straw. I hope more analyses are carried out before it is ever approved by a regulatory agency in the developed world. COVID-19 is a ravaging pandemic, taking lives and freedom at the same time. However, it doesn't give us the excuse to relinquish our high standards in scientific and medical practice.
*By the way, for those of you referring to COVID-19 as a 'global pandemic', that's a misnomer. The definition of the word 'pandemic' already covers the fact that it affects the globe, not just a single geographical region.
**Polio is a very serious disease, which can lead to encephalitis (brain inflammation) and a debilitating condition called transverse myelitis, where patients cannot move properly due to the damage of nerve endings. There is great overall (both economic and psychological) burden of the disease worldwide.
References and Further Reading:
[1] Voysey M, Clemens SAC, Madhi SA, et al. (2020). Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. (published online Dec 8.) https://doi.org/10.1016/S0140-6736(20)32661-1.
[2] Boseley S. (2020). Oxford/AstraZeneca Covid vaccine has 70% efficacy, full trial data shows. The Guardian. Retrieved 10 December 2020, from https://www.theguardian.com/world/2020/dec/08/oxford-astrazeneca-covid-vaccine-has-70-efficacy-full-trial-data-shows.
[3] Quinn B. (2020). 'It's a great day': Oxford coronavirus vaccine volunteers on trial data. the Guardian. Retrieved 10 December 2020, from https://www.theguardian.com/world/2020/nov/23/great-day-oxford-coronavirus-vaccine-volunteers-react-trial-data-astrazeneca-covid.
[4] Bundock L. (2020). COVID 19: Oxford/AstraZeneca vaccine is safe and effective, independent analysis finds. Sky News. Retrieved 10 December 2020, from https://news.sky.com/story/covid-19-oxford-astrazeneca-vaccine-is-safe-and-effective-independent-analysis-finds-12155304.
[5] Offord C. (2020). The Lancet Alters Editorial Practices After Surgisphere Scandal. The Scientist Magazine. Retrieved 10 December 2020, from https://www.the-scientist.com/news-opinion/the-lancet-alters-editorial-practices-after-surgisphere-scandal-67953.
[6] Polio Disease and Poliovirus. CDC. (2020). Retrieved 10 December 2020, from https://www.cdc.gov/cpr/polioviruscontainment/diseaseandvirus.htm#:~:text=Type%202%20wild%20poliovirus%20was,declared%20eradicated%20in%20October%202019.
[7] Venkataswamy MM, Goldberg MF, Baena A, Chan J, Jacobs WR Jr, Porcelli SA. (2012). In vitro culture medium influences the vaccine efficacy of Mycobacterium bovis BCG. Vaccine. 30(6):1038-1049. doi:10.1016/j.vaccine.2011.12.044.
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