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)