Omicron and COVID pills – the beginning of the end?

 Omicron variant

Omicron is the current dominant COVID-19 variant across the globe and in only a few weeks has even outcompeted Delta in the USA. As of January 4^th, 2022, omicron is now estimated to be 95% of new case counts. As the newest COVID variant blazes across the country and the world, by some metrics the pandemic is as out of control as ever. Average daily case counts are at an all-time high, with an exponential increase over the past few weeks. While it is still too early to tell because hospitalizations and deaths trail case counts by a few weeks, those figures have increased at a much slower rate.

Vaccines, Variants, and a Herd (Immunity) of Tigers, Oh My!

After over a year of worldwide shutdown due to the COVID-19 pandemic, the end appears near. Over 1.2 billion doses of vaccine have been distributed worldwide, including over 250 million in the United States. The pandemic is nowhere near over, however, and it is likely that COVID will never actually disappear but instead become endemic, like the flu. There are currently three vaccines authorized for emergency use in the United States, with another widely used in Europe and currently under Food and Drug Administration (FDA) review. Despite the encouraging progress on vaccination, many public health officials are concerned that the global vaccination effort is in a tight race against the potentially dangerous evolution of the SARS-CoV2 virus that causes COVID-19. After all, with more infections comes more opportunity for viral mutations. This post will discuss the available COVID-19 vaccines, the emerging variants, and what we know about the sustainability of immunity.

 

Background

In order to appreciate the differences among vaccines, an understanding of the “central dogma” of molecular biology is necessary. The central dogma summarizes how genetic information becomes functional molecules that impart function to a cell. The centra dogma is as follows:

DNA -> RNA -> Protein

DNA is the genetic code of an organism – aside from random mutations, DNA is identical in every cell in your body, and contains every gene that every cell may ever need. What determines whether a particular cell is a skin cell or a liver cell or a heart cell, for example, is the “expression” of particular genes. Gene expression means the selective coding of particular DNA gene sequences as a template to create RNA in a process called transcription. This RNA, known as messenger RNA or mRNA, is then used as a template for a sequence of protein building blocks in a process known as translation. Completed proteins then carry out various functions that define the cell type. Figure 1 presents a diagram demonstrating this process. DNA is much more stable than RNA or proteins, which is why it serves as the permanent genetic template for every cellular function in your body. RNA and proteins can be easily degraded and therefore must be replenished to continue carrying out their functions.

Figure 1: The central dogma of molecular biology (Source: Khan Academy)

 

Traditional vaccines work by exposing the immune system either to the pathogen (disease-causing virus or bacteria) itself or a surface protein from the pathogen that can be recognized by the immune system to protect against the actual infectious agent. The surface protein or protein segment recognized by the immune system is called an antigen. The first two approved vaccines, by Pfizer-BioNTech and Moderna, utilize a new technology that relies on RNA instead of traditional methods. This RNA strand contains the cellular instructions for an antigen of SARS-CoV2, the spike protein, which helps the virus bind to cells. The other two broadly available vaccines are by AstraZeneca and Johnson & Johnson. These vaccines use a viral vector (adenovirus) containing DNA coding for the same spike protein (although the specific sequences may differ). The adenovirus (which is not able to replicate) then injects individual cells with this DNA. While use of viral vectors is also relatively new, unlike RNA vaccines they have been used for previous outbreaks such as Ebola. Essentially, all these vaccines work similarly by utilizing the molecular sequences that code for the protein antigen, differing primarily by whether they rely on the DNA or RNA step in the central dogma. All except Johnson & Johnson involve a 2-shot regime. As stated above, DNA is much more stable than RNA, which is why the two mRNA vaccines must be stored at freezing temperatures while the Johnson & Johnson vaccine can remain indefinitely in a refrigerator.

 

Blood clots from the COVID vaccine... a real concern, or statistical noise?

Back in March, several European nations paused use of the AstraZeneca vaccine based on concerns about case reports of blood clots in recently vaccinated individuals. The specific blood clots formed in several of the patients were a rare and dangerous type of clot known as cerebral venous sinus thrombosis (CVST), resulting in strokes and occasionally seizures in patients. Whether in the brain or elsewhere, these blood clots were especially unusual because they were associated with low platelets (a condition known as thrombocytopenia) and sometimes bleeding. Even more concerning, the specific blood clot formed in many of the patients was. The same phenomenon was later observed with the Johnson & Johnson vaccine, resulting in a pause in the US in mid-April. Interestingly, almost all of the cases were identified in younger females aged 18-48 (although one case in a younger man has since been reported, as well as an earlier male case during clinical trials).

CFR, IFR, and You: What is the true COVID-19 death rate?

Approximately 6 months off from the official start of the COVID-19 outbreak in China (although the actual start of the outbreak is debated) and over 3 months from the initial nationwide shutdown in the United States, there is much uncertainty as to the true mortality rate of the disease. It is first important to define terms, as there are different types of “mortality” or “fatality” rates.

Defining Case Fatality Rate vs. Infection Fatality Rate

As shown in Figure 1, the reported number of COVID-19 cases does not necessarily represent the true number of infected individuals. The confirmed number of cases (positive tests for active infection) is smaller than the number of probable infected (sick patients believed to be infected based on symptoms and likely exposure but who never received a diagnostic test), which is smaller than the actual number of total infected individuals.

Figure 1. Relationships between measured number of COVID-19 cases via different metrics and number of deaths (not necessarily to scale)

A case fatality rate(CFR) is the proportion of deaths from a disease compared to the number of people diagnosed.

An infection fatality rate (IFR) is the proportion of deaths among all infected individuals, in other words the true fatality rate. While related to the CFR, an IFR attempts to estimate the mortality rate including non-diagnosed cases (e.g. not tested, asymptomatic). An IFR should be lower than the CFR, since the denominator would be expected to be larger.

 

Visually, these can be represented as shown in Figure 2 below, based on the relative differences in confirmed vs. total cases as shown in Figure 1. Note that deaths can be scored as either confirmed deaths or probable deaths. As testing becomes more widespread, the difference between “confirmed” and “total” infected shrinks, as does the difference between CFR and IFR.

Figure 2. Visual representation of Case Infection Rate (CFR) and Infection Fatality Rate (IFR)

Going Vape Shit Over E-cigarettes

Vaping History and Use

According to VapingDaily.com, vaping is “the act of inhaling vapor produced by a vaporizer or electronic cigarette. The vapor is produced from a material such as an e-liquid, concentrate, or dry herb.” An important distinction from traditional “smoking” is that vaping refers to breathing in heated water vapor, NOT the incineration products of a burning reaction. The earliest form of vaping traces all the way back to 440 BC, with stories of people inhaling the resulting vapor from marijuana placed onto hot stones. The hookah, invented in 1542, is also analogous to vaping. The first true vaporizer was invented by a Korean war veteran in 1962, although the idea for an e-cigarette comes from 1927. The modern e-cigarette was created by a Chinese pharmacist in 2003.

E-cigarettes (or “vapes”) work by using a battery to heat up vaping material until it becomes an inhalable vapor. While waxy concentrates and dry herb can be vaporized as well, vapes typically utilize an easily vaporizable liquid such as propylene glycol or vegetable glycerin. Flavoring and drugs, typically nicotine, can be dissolved within this liquid for easy inhalable delivery to the user upon heating. Often, the dissolved drug is nicotine. The presence of nicotine in these cigarettes is both functionally useful and problematic, depending on the user. Vapes come in many sizes, styles, and options (Figure 1). These options include various accessories and cartridges that may contain flavoring or recreational drugs.

Figure 1: Examples of vape designs. Source: https://www.cdc.gov/tobacco/basic_information/e-cigarettes/pdfs/Electronic-Cigarettes-Infographic-508.pdf

Nicotine in E-cigarettes

E-cigarettes can serve as an effective smoking cessation method. Use of nicotine e-cigarettes resulted in 7% of regular smokers remaining abstinent from smoking after 6 months, slightly higher than the rate from nicotine patches (5.8%) and higher still compared to e-cigarettes without nicotine (4.1%). Additionally, while the toxicity of vapes can vary depending on what they contain and the mechanics of heating, the UK government declared in 2015 that use of e-cigarettes is approximately 95% less harmful than traditional cigarettes. Heating of vape liquid can result in exposure to various carcinogenic metals and other toxic compounds, however vaporization is likely to produce much less harmful volatile organic compounds than traditional cigarettes. This is likely due to both the absence of tobacco and reduced release of chemical degradation products that would be produced from burning.

Vaping has been on the rise for the past several years, especially among young people. According to Pew Research (Figure 2), the percentage of 12^th graders who report having vaped at least once in the past month doubled from less than 14% to 27% between 2016 and 2018. A similar trend was presented in a study by the New England Journal of Medicine, which reported prevalence increases from 11.0% to 25.4% among 12^th graders between 2017 and 2019 (Figure 3). While the inclusion of nicotine in e-cigarettes can be beneficial for current smokers aiming to quit, it is obviously problematic for young non-smokers. In addition to promoting nicotine addiction in general, there is evidence that e-cigarette use is associated with a much greater likelihood to begin smoking traditional cigarettes as well (however this association cannot establish a causal relationship).

EVALI outbreak and causes

Beyond only these concerns, 2019 brought a very concerning spike in e-cigarette or vaping product use-associated lung injury, formally coined as EVALI. As of December 27, 2019, EVALI has resulted in 2,561 hospitalizations and 55 deaths. While cases have been gradually increasing since 2017, there was a sudden outbreak beginning in June 2019 prior to a decline in new cases as of September 2019. As described above, modern e-cigarettes have been in use since 2003. Based on this timeline, what could have been the cause? Could it simply be due to the rapid increase in prevalence of use (Figures 2-3), or did something change about either the e-cigarettes themselves or their content?

Figure 2: The percentage of 8^th grade, 10^th grade, 12^th grade, and college students who self-reported vaping during the last month. The highest rate exists among 12^th graders, however all grades increased at a similar rate between 2016 and 2018. Source: https://www.pewresearch.org/fact-tank/2019/09/26/vaping-survey-data-roundup/

Figure 3: Prevalence of nicotine vaping among adolescents over different time intervals. Results are presented for 2017, 2018, and 2019. Source: https://www.nejm.org/doi/full/10.1056/NEJMc1910739

An important consideration in discovering the cause of the outbreak was the fact that the outbreak was restricted to the United States, despite being used throughout the world. This suggested that the source of EVALI was not inherent to e-cigarettes overall, but must be something that is specifically being used in the United States. A CDC investigation found that the vast majority of EVALI cases were associated with products containing THC, the active ingredient in marijuana that makes you high. The presence of the chemical vitamin E acetate was a common component in the e-liquid of these THC-containing vapes. Researchers also identified vitamin E acetate in the lung fluid of 94% of examined patients, compared to 0% of controls. Vitamin E is naturally found in foods and also can be useful as a supplement (despite some risks), however the acetate form appears to be the cause of lung toxicity from vaping when inhaled.

Targeting to Youth

As would be expected, the majority of THC vapes are purchased off the black market and therefore are likely not subject to much quality control or oversight. Black market products are most likely to be used by youths who do not have legal access to legal products. Therefore, EVALI is even more concerning in that it is likely to affect children. Even certain legal products are more likely to be used by younger customers, including those who may have not otherwised smoked. Even though many of the major e-cigarette companies now claim that their products are only for adults, the use of social media advertising and fun flavors suggests that targeting youths was at least once an active strategy.

As discussed above, e-cigarettes may have actual health benefits for adult smokers and remain a potentially safer recreational option for all adults. However, in response to the EVALI outbreak and the rapid increase in youth usage, the FDA and local health departments have been under strong pressure to more regulate vaping access overall. San Francisco completely banned the sale of e-cigarettes to anyone beginning in 2020 and other localities are likely to follow. Most recently, President Trump announced on the last day of 2019 that he was planning to ban all e-cigarette flavoring except tobacco and menthol. Allowing these two flavors to remain, especially menthol, was a compromise in favor of both vape shops as well as adult customers who claim they are trying to get away from the tobacco smell and flavor. Time will tell whether this partial ban will adequately minimize youth vaping, however any regulation cannot prevent access to black market products.

For an interesting discussion with some more details on the issue from a nuanced perspective, I highly recommend the Freakonomics podcast episode about vaping regulation. The podcast additionally dives into some of the nuances of previous and existing FDA regulation of e-cigarettes, and how that actually restricts the ability of vape companies to advertise only as a smoking cessation aid.

Love Has No Labels, but GMO Foods Soon Will: The National Bioengineered Food Disclosure Standard

The relative benefits vs. risks of widespread bioengineered crops and other food sources is an often aggressively-debated issue between scientists, the agricultural industry, and consumers. Genetically Modified Organisms, or GMOs, are defined by the European Food Safety Authority as “an organism in which the genetic material has been altered in a way that does not occur naturally through fertilization and/or natural recombination. GMOs may be plants, animals or micro-organisms, such as bacteria, parasites and fungi.” “Genetic Engineering” (GE) is an alternative term used to refer to the manipulation of these species at the DNA level to produce or promote particular traits. GE crops are thus “genetically engineered”. There has been public resistance to the proliferation of GMO food, despite organizations such as the American Medical Association (AMA) and the American Association for the Advancement of Science (AAAS) declaring that genetically engineered foods do not present any appreciable risks.  Nonetheless, a large majority of Americans are in favor of GMO labeling in food products. While the AMA, AAAS, and other scientific organizations argue that GMO labeling will inappropriately imply that GMOs cause harm, consumer advocacy groups contend that people have a right to know what they are eating.

Ignore At Your Own Risk: A Risk Management Perspective on Climate Change

Gallons of digital ink has been spilled discussing and debating the legitimacy of concerns over climate change and global warming. Unfortunately, like many internet debates, both sides of the argument at times rely on emotional arguments, unrealistic assumptions, and overly simplistic outlooks, with a noticeable lack of nuance. While there is overwhelming scientific consensus that global climate is definitively warming, this alone provides only a small part the story. The Earth is indeed warming, but so what? Does it matter, and if so what are possible solutions?

Global warming has environmental, economic, and societal impacts. The projections of the specific timing and severity of those impacts result in a wide range of values, however. Given this, How can we pinpoint the required industrial and societal changes necessary for reducing those impacts if we cannot precisely quantify those impacts in the first place? An effective climate change policy must account for numerous scientific and socioeconomic uncertainties that are likely to substantially affect both the costs and benefits of any policy action.