And the award for the top fizzy drink of the year is...the Pfizer and BioNTech Vaccine. Appalled by the methodological errors and inconsistencies of thee Oxford COVID Vaccine Trials, I was genuinely downhearted. I was convinced that political propaganda and sanitary urgency have 'oversold' sub-par trials and that it's never possible to synthesise a safe and efficacious vaccine within a few months. However, I was wrong. Pfizer's vaccine, containing BNT162b2, can be deemed as a vaccine which has the genuine prospect of success and universal applicability. [1]
At first, I greeted it with the same amount of hostility and apprehension. But then, as I read the paper, I felt a long-lost sense of optimism gushing down my veins. Of course, there remain issues that are yet to be resolved. It doesn't mean that we have finally found the 'one' and the world is a much better place. Long-term analyses are still crucial and improvements have to be made for assessing the applicability of the vaccine to different patient subgroups. However, in the general sense, the analyses run by the Pfizer trial make much more sense than the Oxford ones [2]. In this article, I aim to give an account on various aspects of the paper and my comments pertinent to each section. I strive to be unbiased in my prose so as to critically assess the efficacy and practical benefit of using the vaccine on a community-wide basis.
The Paper [1]:
What this vaccine is trying to achieve: Stimulation of the vaccinated individual's immune system through the production and presentation of viral antigens, leading to a more robust response upon the individual's second exposure to the virus (intended: in the community).
What this vaccine contains: BNT162b2, a lipid nanoparticle-formulated, nucleoside-modified RNA sequence which encodes the SARS-CoV-2 full-length spike;
Again, this chain of words might mean nothing to most people, just like the contents of the Oxford COVID Vaccine. Suffice to say, the underlying mechanisms of the two vaccines are identical, but different avenues are adopted to reach there. They both strive to produce the antigen* (or identity badge) of the virus, SARS-CoV-2 (the microbe causing COVID-19) which stimulates the body's immune response. Once the immune system gets triggered by the antigen the first time, the process of mobilisation starts. This is beneficial. If the vaccinated individual gets out in the wild (aka the community) and unfortunately encounters the virus in its natural habitat, the entry of the virus immediately presses the red button. The mobilised troops of the body's immunity launches a much more vibrant and dynamic, full-scale defence which tears the viral forces to their core. Of course, a vaccine is not necessary to stimulate the response. Many individuals who contracted COVID-19 remain asymptomatic or only present with mild symptoms. As published on the BMJ, 78 per cent of new cases of COVID-19 recorded by China in the 24-hour period leading up to the afternoon of 1 April (this year) are asymptomatic. [3] Moreover, a study, based on a Chinese cohort, shows that the case fatality ratio stands at 1.38 per cent in general. [4] Individuals of immunocompetent status (whose immunity is fine) just need more time for the immune system to get mobilised. Of course, this also explains why vulnerable groups, defined by age (the elderly) and health status (afflicted by immune-related diseases such as diabetes mellitus and HIV), when afflicted by the virus, report higher rates of mortality. The case fatality ratio for those aged above eighty years old is 13.4 per cent. [4]
Diagram showing protein synthesis (Courtesy of Pearson Education).
An mRNA sequence, in contrast to a DNA sequence, is crucial for the synthesis of proteins. This goes back to the age-old idea of the 'central dogma', which means that amino acid (the basic unit of protein), DNA and RNA are best friends and information can be transferred from one source to another. There are mechanisms in place for them to switch from one to another. mRNA, a product of a process called transcription, is followed by translation. This takes place in a safe cosy spot called the ribosome (they can be free-floating ribosomes in the cellular cytoplasm, or the ribosomes attached to the endoplasmic reticula floating close to the nucleus). The ribosome contains rRNA (ribosomal RNA) and ribosomal proteins. [5] The former is important for the physical and chemical attractions required for translation to take place. tRNA molecules are attracted to the ribosome and create an opportunity for exchange. Codons (one codon = three consecutive bases in the mRNA sequence) are exchanged for the amino acid molecules attached to the other end of the tRNA molecules. The amino acids then form bonds with each other. As things get more complicated (all the cosying up, cuddling, twisting and perspiration-inducing activities), chains of amino acids form more complex structures until proteins are formed.
This is only slightly different from the Oxford COVID Vaccine method. In that trial, [2] they use an adenovirus-based vector to transfer the tiny genetic sequence required (DNA, not RNA - Adenoviruses are DNA-based viruses; however, viruses such as HIV are RNA-based) to the body cells, so that body cells synthesise, with the cornucopia of resources they have, proteins as the tiny genetic sequence is fused with the body cell's own DNA. The Pfizer Vaccine uses an mRNA - a shortcut. As the mRNA is absorbed by body cells, it doesn't go through the exhausting process of combining with the genetic material of the body cell, waiting to be synthesised. It jumps straight to the ribosomes present in the cytoplasm and gets converted into amino acid sequences and eventually, proteins. Such proteins (in this case, antigens of the virus SARS-CoV-2) are going to be brought up to the cellular surface, triggering immune activation as they bind with the receptors present on the surfaces of immune cells.
Two Major Groups for Comparisons: BNT162b2 Vaccine (Intervention Group), Saline placebo (Control Group) [2 doses each].
Personally, I think this makes way more sense than the Oxford protocol, which insists on the use of a vaccine for the intervention group and a meningococcal vaccine for the control group**. [2] I do appreciate their efforts in trying as much as possible to create a 'quasi-COVID-vaccinated' situation for those in the control group, minimising the placebo effect. This effectively reduces the placebo effect to a greater magnitude than adopting a saline placebo, since the control group does experience adverse effects after vaccination. However, is patient safety capable of being compromised in the name of greater scientific accuracy? A saline placebo can, at most, lead to localised reactions due to the 'prick' - we are talking about localised pain at the site of injection, bleeding and the sort. With a meningococcal vaccine, it can lead to various neurological manifestations (most common of which are Guillain-Barre Syndrome, an autoimmune disorder which starts from the peripheries; and seizures) and anaphylaxis (a generalised, severe immune reaction which can lead to death if untreated) [6]. I think everything comes with a line. For the Oxford COVID Trial, they stress on scientific accuracy on points that just don't matter. Conversely, for aspects which might tremendously affect the accuracy of the results, they lack the incentive to improve.
Numbers of participants (by group) having taken both doses:
Intervention Group: 18,556;
Control Group: 18,530.
The numbers here are significantly greater than the individual trials of the Oxford COVID Vaccine Study. As the numbers are greater, the results garnered from the Pfizer trial are, regardless of socio-demographic and medical differences, more representative and reproducible. For example, the UK Trial only has: 1367 + 1374 + 2377 + 2430 = 7548. The first two numbers come from the number of participants in the trial who received Regimen One (lower dose/standard dose), whereas the last two numbers, Regimen Two (standard dose/standard dose). For more details, refer to my critique published earlier. The discrepancies in dosage are a major point of criticism.
Interval between 1st and 2nd doses: 21 days (in all scenarios);
This is much better than the Oxford COVID Vaccine Trial, where the interval is not fixed. There is an expectation that the 2nd dose is carried out within four weeks after the administration of the first dose, but there is no guarantee in some trials. This lack of uniformity introduces a source of confounding.
Outcomes:
(a) Safety:
Solicited, specific local or systemic adverse events and the use of anti-pyrexic medication (suppressing fevers, such as paracetamol) or painkillers within 7 days of the administration of each dose;
Unsolicited adverse events 1 month and 6 months after the administration of the 2nd dose.
(b) Efficacy:
Primary: (i) Efficacy of vaccine against confirmed COVID-19 with onset at least 7 days from the 2nd dose in participants who reported no signs of COVID-19 within 7 days from the 2nd dose; (ii) efficacy in participants with and without evidence of prior infection;
Major Secondary: the efficacy of the vaccine against severe COVID-19.
Severe COVID-19, is defined by the study as confirmed COVID-19 (using studies such as NAAT) plus one of: (a) significant neurological, hepatic or renal dysfunction (acute), (b) shock, (c) respiratory failure, (d) severe systemic illness (affecting multiple systems in the body), (e) admission to the Intensive Care Unit, or (f) death.
Side effects in patients with prior diagnosis of HIV are also included. They are analysed and reported separately. This is to be welcomed since the Pfizer Trial recognises that apart from young, fit, white healthcare workers, there are medically marginalised communities in society and the vaccine is for the many, not the few. It is quite unfortunate that the Oxford COVID Trial ignores this one important fact of life.
Participant Profile:
In general, individuals aged 16 years or above, who were healthy or afflicted by chronic medical conditions, exemplified by hepatitis C, and HIV, are eligible for the trial. These chronic medical conditions must be stable and well-controlled. The only exclusion criteria reported on the paper include the diagnosis of an immunocompromising condition (leading to weakness in the immune system), prior diagnosis of COVID-19, and the reception of immunosuppressive therapy (this applies to, say, patients with lupus who are receiving drugs such as steroids and mycophenolate mofetil, which are effective in dimming down the immune response).
The inclusion of those with chronic medical conditions is to be greatly welcomed. This does not contradict the exclusion of those with a diagnosis of a condition which impairs the immune system, since the exclusion criterion applies mostly to those who have not controlled their conditions well. This is important. It introduces a firm line in order for the results of the study to be reproducible in larger cohorts. Take Hepatitis C as an example. The definition of 'controlling' Hepatitis C well is when the viral load is so low that it cannot be detected in the bloodstream. This is also known as achieving the serologic viral response. While the presence of the virus itself is not sufficient to cause problems in the immune responses of such patients upon taking the COVID vaccine, sub-analyses can be run to assess how different these patients respond to the vaccine as compared to other groups. For those having Hepatitis C, there must be some sort of predilection, since not everyone, upon being exposed to the Hepatitis C virus, contracts Hepatitis C. This predilection can be contributed by underlying factors such as genetic mutations and so forth. By enlarging the cohort size and recruiting a more diverse cohort, they are essentially seeing if the vaccine works similarly in these subgroups as compared to the mainstream.
This level of liberty stands in contrast to the massive list of restrictions, in support of an unrealistic standard of homogeneity, presented in the Oxford COVID Vaccine Trial. In that trial, those with chronic medical conditions, such as coronary heart disease and cirrhosis, are mostly excluded from the trial. The extremeness of the exclusion criteria can be illustrated amply by the exclusion of those with 'any clinically significant abnormal finding on screening biochemistry, haematology blood tests or urinalysis' and 'Any other significant disease, disorder or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study or impair interpretation of the study data'. [7] Such terms are used in such a liberal and ambiguous manner that means everything boils down to clinical judgment, which may not be as standardised as one might envisage.
[1]
In terms of the age group, there is an even split between individuals aged above and below 55 years. This is much better than the Oxford COVID Vaccine Trial, which in majority recruited participants in the age group 18-55 years. Patchy recruitment of participants has rendered those aged above 55 years an anomaly rather than the norm. The median age of participants in this trial is at 52 years, attached to a huge age range. This is representative of the general population. Even though the mortality rate of COVID-19 is 8.1 times higher in patients aged 55-64 years, and more than 62 times higher in those aged over 65 years, than those aged 54 years or younger [8], this is the best compromise we can get since we cannot solely recruit those aged above 65 years for the trial. A balance has to be struck.
The problems seen in the Oxford COVID Vaccine Trial are still present here. For instance, in terms of racial diversity, the cohort remains rather homogenous, although over one-fifth of the cohort reports hispanic ancestry. It has to be noted that participants can be both white and hispanic, since the term 'hispanic' is both a cultural and racial designation. Nonetheless, the magnitude of this issue is smaller than that in the Oxford trial. The second issue is the uneven distribution of participants. Personally, I think it would be much better if each country is equally represented in the study. However, regarding the administrative side of affairs and the rapid escalation of the pandemic, perhaps recruitment of participants in the US is easier than that in the other three countries. Notwithstanding the attractiveness of this line of reasoning, there is no room for complacency. Long-term studies require equal representation from multiple countries in order to see if the vaccine, intended to be distributed and utilised globally for global communities, works in different contexts, not just limited to a particular subgroup.
Results and Discussion:
VACCINE EFFICACY
[1]
There are two items on the list - going back to the primary efficacy outcomes, the first one represents those without evidence of infection, while the latter, with and without. The vaccine efficacy rates are largely comparable, at respectively 95 per cent and 94.6 per cent. They are much higher than the Oxford COVID Vaccine Trial results - where the vaccine efficacy (in general) stands at roughly 70 per cent. [2]
However, this is only the general result. Does the vaccine work equally well in particular strata of the community?
[1]
The results shown in this table are very encouraging. At the same time, there are noticeable problems that cannot be neglected. The efficacy rates for most subgroups are above 90 per cent. Significantly, despite an increase in age, there is no remarkable decrease in the efficacy of the vaccine. The gender gap is insignificant, considering the fact that the vaccine efficacy ranges overlap to a great extent. The racial gap is also minimal. The vaccine is largely efficacious in blacks and Hispanics. As reported in my article critiquing the Oxford COVID Vaccine Trial, ethnic minorities in Western countries are at higher risk of contracting COVID and hospitalisation due to it than the white population. [9] Thus, it can be reasonably deduced that racial differences exist in the realm of immune responses against COVID and mechanisms for the development of COVID in the body. Seeing that the vaccine works equally well in these ethnic subgroups means that such racial differences do not prevent these individuals from deriving full benefit from vaccination. There is also minimal difference between countries in terms of vaccine efficacy, due to the vastly overlapping confidence intervals.
However, one cannot only interpret the rates of vaccine efficacy without looking at the gross values. Statistics can be easily twisted and manipulated to produce the results that we want to see, rather than the results that reflect reality. Reading in conjunction with the table above which presents with the demographic features of the cohort, we start to see problems. For patients aged 65 years or above, the confidence intervals start to get wider, peaking in the age group => 75 years. The confidence interval there ranges from -13.1 to +100. This is due to the fact that there is minimal difference (5 cases) in cases of COVID-19 infection in participants aged 75 years or above in the 2 groups (intervention and control). The number of participants aged 65 years or above is also regrettably smaller than those under. This gives rise to rather weird statistical results. The same goes with the racial subgroups. The confidence intervals for blacks/African Americans and 'all others' are respectively 31.2-100 and 22.6-99.8. These are enormous as compared to the ones of other subgroups. This can be traced back to the fact that only 9.2 per cent and 7.9 per cent of participants in the cohort are respectively black and 'all others' (non-white, non-black, non-hispanic). In terms of country, Brazil has the second smallest representation in the cohort, at approximately 6 per cent. This explains why the width of the confidence interval stands at 91.6 per cent.
As I mentioned in my other article, the study does not end here. To produce more representative, reproducible and accurate results, it has to last for more than a meagre few months. A longer follow-up period, measured in years, is required to deduce the full immunological protection stimulated by the vaccine. More participants from underrepresented subgroups, such as ethnic minorities in the United States, people from outside the United States, as well as participants aged over 65 years, have to be recruited to generate a more comprehensive picture.
ADVERSE EVENTS
[1] This figure shows the systemic effects within 7 days after the administration of the vaccine/placebo (both dose 1 and dose 2).
[1] This figure shows the local effects within 7 days after the administration of the vaccine/placebo (both dose 1 and dose 2).
In terms of local events, no remarkable difference is observable across doses (1 and 2) and age groups (above & below or equal to 55 years). Having said that, more participants younger than 55 years report pain (after first dose: 83 per cent, after second dose: 78 er cent), as compared to those above (after first dose: 71 per cent, after second dose: 66 per cent). It has to be mentioned, though, that pain is a subjective concept. The same amount of pain afflicted can be interpreted differently depending on the person. Especially when the differences are small and the follow-up period is limited to 7 days, no definite conclusions can be drawn. Redness and swelling are generally rare, in both the intervention and control groups. Pain at injection site is the most common local adverse event in both the intervention and control groups, but much more significantly so in the intervention group.
In terms of systemic events, in general, fever and vomiting are the least common adverse events. Fatigue, headaches and chills are the most common.
The incidence of systemic adverse events (both in general and individual items), is higher in the intervention group than the control group. The differences are statistically significant (i.e. the confidence intervals do NOT overlap) especially in fatigue, headaches, fever, muscle pain and use of anti-pyrexic medication across doses and age groups.
More participants in the 16-55 age group present with moderate and severe incidents of fatigue, headaches and chills, than those aged above 55 years.
More participants report fatigue, headaches and chills after the second dose, than after the first dose, regardless of age.
Use of anti-pyrexic medication is more common in participants aged 16-55 years, than above 55 years.
In terms of severe adverse events, the incidence is higher in the intervention group. For instance, 64 participants in the intervention group present with lymphadenopathy (reflective of enhanced immune reactions following vaccination) as compared to 6 in the control group. This is an expected result.
There are no incidents of transverse myelitis, or other neurological complications reported, in contrast to the Oxford COVID Vaccine Trial.
There are a total of 6 deaths (2 in the intervention group and 4 in the control group) but none of which are related to vaccination or COVID-19 infection.
There are 4 incidents of serious adverse events, which are respectively: right leg paraesthesia, arrhythmia, shoulder injury secondary to vaccination (since the vaccine is administered over the deltoid muscle) and right axillary lymphadenopathy (it is unknown why the paper reports this and general lymphadenopathy differently. This might be due to the unique distribution of the lymphadenopathy or the extent of it). Moreover, right leg paraesthesia might be indicative of a neurological deficit secondary to provoked immunity in a participant who has high autoimmune tendency. This is merely a hypothesis since it is not elaborated in the paper. However, more studies have to be performed to ensure that the vaccine is safe (or can be rendered safe) in patients with well-controlled autoimmune conditions, including mild asthma, dermatitis and food allergies.
Fortunately, lymphadenopathy generally resolves within 10 days from onset. Moreover, most adverse events resolve within a couple of days. The vaccine therefore has an acceptable safety profile in general.
The study has ambitiously wanted to follow participants in the intervention group for 2 years after having administered the second dose of vaccine, so as to generate a more comprehensive safety profile. This is lauded. Practical concerns have barred it from following those who are in the control group. There are also additional analyses performed on adolescents and pregnant women with regard to the safety profile of the vaccine.
Concluding Remarks: I am pleasantly surprised by how well-thought this trial is. It is free from many of the ambiguities and arbitrariness of the Oxford COVID Trial. The results presented are more favourable and the cohort is more diverse, although they do have to work on recruiting more participants from outside the US and improving the racial make-up of the cohort. More participants above the age of 65 years also have to be recruited so as to paint a clearer picture of its efficacy in elderly patients, who are a vulnerable segment amidst the COVID-19 pandemic. It is encouraging to note that vaccine efficacy is quite uniform across subgroups and the study group aims to look into the safety profile of the vaccine in other strata of the population, including pregnant women. Pregnancy and immunity affect one another and this can lead to variant effects of the vaccine. [10]
Another subgroup worth analysing: The Sleep-Deprived-
This issue has not been explored by any of the vaccine trials (COVID) I have read. However, sleep deprivation is another pandemic and afflicts many people annually. A study in Netherlands shows that 43.2 per cent of the cohort state they do not have sufficient sleep. The prevalence of sleeping disorders is shown by the same study as 27.3 per cent. [11] It is shown that variations in sleep quality (intrinsically related to the amount of sleep received) is associated with health outcomes. The relationship is strong for mental health outcomes and moderate for cognitive and physical health. [12] There are also correlations between sleep deprivation and immune function. In Professor Matthew Walker's book, 'Why We Sleep' [13], he wrote about a study performed in 2002 regarding the relationship between sleep duration and the immune response generated by vaccination. Participants were divided into two groups: (a) receiving 4 hours of sleep a night for 6 nights; (b) receiving 7.5-8.5 hours of sleep a night for 6 nights. A standard flu vaccine was administered after the period. Subgroup (a) reported an immune reaction 50 per cent less robust than that of subgroup (b). In another study mentioned in the book, one night of 4-hour sleep is enough to swipe away 70 per cent of Natural Killer Cells (one of the colonels you've seen earlier in the immune system) as compared to those having relished an 8-hour sleep.
Regarding the role of sleep deprivation, it is sensible to stratify participants into groups according to their sleep patterns and assess whether this vaccine still works as efficaciously in those who sleep less, say four to six hours a night for the past month, as those who sleep more. After all, a COVID vaccine may work differently than a flu vaccine and Walker's results may not be replicated in the Pfizer vaccine. Also, back to the realm of health economics, if it is established that those who are severely sleep-deprived are less likely to derive the full benefit of the vaccine, resources can be concentrated on those who sleep more.
*Antigen is usually a protein on the surface of the microbe (this is not limited to viruses; that's why the immune system can protect us against microbes in general, not just viruses). In this case, it is a spike protein. Immune cells have receptors which are capable of being bound to this antigen. This triggers a chain of biochemical reactions, culminating in the rapid deployment of forces - chiefly led by the colonels: Natural Killer Cells, T Killer Cells and, B Effector Cells (only they produce antibodies against the microbe; the other two kill the cells who harbour the virus, aka traitors).
**This point is very important. The Oxford COVID Vaccine paper published on The Lancet [2], shows the aggregated results of four different trials. There are different protocols present for different trials. For the UK Trials, the meningococcal vaccine is used as a control. For the Brazilian Trial, the meningococcal vaccine is used as the control for the first dose. Saline is the control for the second dose. For the South African Trial, saline is used as the control throughout. Call me a purist, but such inconsistencies might lead to discrepancies impugning the reliability and accuracy of results. In the Pfizer study, there is only one placebo used for the control group.
References and Further Reading:
[1] Polack F, Thomas S, Kitchin N et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine. 2020. doi:10.1056/nejmoa2034577.
[2] Voysey M, Clemens SAC, Madhi SA, et al. 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 8 Dec 2020.) https://doi.org/10.1016/S0140-6736(20)32661-1.
[3] Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicateBMJ 2020; 369 :m1375.
[4] Verity R, Okell L, Dorigatti I et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis. The Lancet Infectious Diseases. 2020;20(6):669-677. doi:10.1016/s1473-3099(20)30243-7.
[5] de la Cruz J, Karbstein K, Woolford JL Jr. Functions of ribosomal proteins in assembly of eukaryotic ribosomes in vivo. Annu Rev Biochem. 2015;84:93-129. doi:10.1146/annurev-biochem-060614-033917.
[6] Myers TR, McNeil MM, Ng CS, Li R, Lewis PW, Cano MV. Adverse events following quadrivalent meningococcal CRM-conjugate vaccine (Menveo®) reported to the Vaccine Adverse Event Reporting system (VAERS), 2010-2015. Vaccine. 2017;35(14):1758-1763. doi:10.1016/j.vaccine.2017.02.030.
[7] A Study of a Candidate COVID-19 Vaccine (COV001) - Full Text View - ClinicalTrials.gov. Clinicaltrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04324606. Published 2020. Accessed December 12, 2020.
[8] Yanez N, Weiss N, Romand J, Treggiari M. COVID-19 mortality risk for older men and women. BMC Public Health. 2020;20(1). doi:10.1186/s12889-020-09826-8.
[9] Sze S, Pan D, Nevill C et al. Ethnicity and clinical outcomes in COVID-19: A systematic review and meta-analysis. EClinicalMedicine. 2020:100630. doi:10.1016/j.eclinm.2020.100630.
[10] Mor G, Cardenas I. The immune system in pregnancy: a unique complexity. Am J Reprod Immunol. 2010;63(6):425-433. doi:10.1111/j.1600-0897.2010.00836.x.
[11] Chattu VK, Manzar MD, Kumary S, Burman D, Spence DW, Pandi-Perumal SR. The Global Problem of Insufficient Sleep and Its Serious Public Health Implications. Healthcare (Basel). 2018;7(1):1. Published 2018 Dec 20. doi:10.3390/healthcare7010001.
[12] Gadie A, Shafto M, Leng Y Cam-CAN, et al. How are age-related differences in sleep quality associated with health outcomes? An epidemiological investigation in a UK cohort of 2406 adults. BMJ Open 2017;7:e014920. doi: 10.1136/bmjopen-2016-014920.
[13] Walker M. Why We Sleep: The New Science Of Sleep And Dreams. London, UK: Penguin; 2018:182-184.