The human body contains within it as many mysteries as the universe. One mystery of current interest is how immunity works against Covid-19. The pandemic is showcasing the complexity of the immune system and the current gaps in our understanding. Despite this uncertainty, whether we compare our circumstance to those who weathered pandemics before us or we look to the future, there is significant cause for hope.
Comparing science today to “science” during the Dark Ages has the expected result, but the specifics still have impact. During the black plague in the 1300s people believed that disease was a punishment from God for their sins, and thus reacted to it’s presence either by repenting or accepting God’s will. A second theory common at the time was that the plague was caused by miasma, which loosely translated to ‘bad smells’. After careful study, one of the most medically august bodies at the time, the Faculty of Medicine at Paris, concluded that Earth, Mars and Jupiter were out of alignment which may have caused an “evil vapour” that was responsible for the epidemic. Treatments at the time focused on balancing the humors that were believed to be out of order, with the usual retinue of bloodletting, ingesting things that caused vomiting, and or changing one’s diet.
This pandemic killed between 75 and 200 million people in Eurasia and North Africa. Scientists now believe that the plague was caused by a bacterium that was transmitted through fleas who traveled on the backs of black rats, a fact first discovered hundreds of years after the plague claimed so many lives. Germ theory, the idea that illness arises from viruses and bacteria, was still almost 600 years away.
By the 1890s scientists discovered useful facts about immunity: that it was created through the activity of antibodies and cells; that vaccines could be used to educate an immune system and provide protection from disease; and that disease itself was often caused by bacteria that produced toxins. They didn’t, however, have all the details nailed down. Dozens of bacterial vaccines were created to combat the Spanish Flu of 1918, but all were ineffective against the virus that killed roughly 50 million people worldwide. Without an electron microscope (invented in 1931), viruses could not be seen. Although scientists had identified other viruses, and in fact knew about RNA, they did not know the cause of influenza. Without the ability to identify the source of disease, there was no way to effectively treat it. Doctors prescribed massive doses of aspirin (30mg daily) to alleviate symptoms, which likely caused more problems than they solved given that today doctors do not recommend taking more than 4 mg. Cinnamon in milk and salt of quinine were also common remedies.
Although the source of disease was sometimes rightly attributed to “a virus”, scientists did not make distinctions between viruses and bacteria. And while antibodies were appreciated for their role in fighting infection, scientists didn’t know how the body produced them. The discovery of T cells, the other major player in adaptive immunity, would not be discovered for another forty years. These significant gaps in understanding of both immunology and virology weakened the effectiveness of the medical response to the Spanish Flu. Public health focused on banning large gatherings and insisting that people use gauze masks when entering public spaces.
Contrast everything that’s come before with our current experience. Roughly a month after the coronavirus started attracting attention in Wuhan, the full genome was sequenced (in January of 2020). Scientists immediately dug through this DNA to determine the proteins it coded for. The process of recreating proteins from genetic code can take years, but the majority of the sequences (70-80%) were similar to the SARS-Cov virus that surfaced in 2003. Many groups of scientists all over the world worked to elucidate the structure of unfamiliar proteins. By February the protein structures that make up the virus were released online. By mid March, scientists began the work of trying to find drugs in the current arsenal that will bind to viral proteins. Although we have not yet found a drug that is highly effective at resolving the virus, many trials are still in process.
Another sign of immunological fluency is the work done by scientists to help severe corona cases in which patient’s immune systems have become overactive, aka a “cytokine storm”. These storms arise as a consequence of the release of too much of a particular chemical messenger (or cytokine). Many different chemical messengers exist, and each encourages the development of different classes of T or B cell activity. Scientists are parsing these pathways to figure out exactly which messengers to dampen without shutting down the entire immune response.
Another step toward freedom from this virus lies in vaccine development. Let’s agree that the job of a vaccine is tricky. An effective vaccine must (1) instigate an immune response in the patient, (2) strong enough to induce the development of a neutralizing level of antibodies, (3) but not so strong as to sicken the patient and induce onerous side effects. Each step in this chain invites its own challenges. Which protein on the surface of the virus should a vaccine target? Which will capture the attention of immune cells and encourage them to mount a defense, even though the protein (usually) cannot provoke disease? Which will induce a high enough level of antibodies to neutralize infection? How long will those antibodies last? Can they uniquely identify the virus?
Despite all of these unknowns, we aren’t exactly starting from scratch in our search for a coronavirus vaccine. Substantial work was undertaken to create a vaccine for SARS-Cov, but ultimately, that work was shelved before a working vaccine was produced. In part this seems to be the case because the progress made to identify a workable vaccine, while successful, had the unfortunate luck of arriving when cases in humans had essentially disappeared. Animal models have been used to test these vaccine candidates, with limited results; these results are limited by the fact that mice tend not to have the same symptoms as humans, and although ferrets do get fevers and coughs, their immune system is less well understood. Papers that consider the status of these vaccines suggest that we’ve learned that (1) the S protein (the spike) can instigate the immune system to respond, (2) vaccines that are administered through the nose may have a bigger impact on the virus than an intramuscular shot, and (3) inducing both B and T cell responses may be required to put the virus down.
Questions about if and how long immunity lasts reflect lessons learned from previously challenging viruses. Antibodies don’t always provide immunity for every virus. For example, with HIV, the virus that causes AIDS, antibodies exist in the systems of people who have this virus, but appear to fail to provide immunity.
In this specific case, it’s believed that this is a consequence of a number of issues. One is the mismatch between the shape of antibodies and the sparse coverage of HIV virus in spike proteins to which antibodies can attach. Antibodies do their best work when both arms of their Y shaped body can attach to a protein on the surface of a virus. But the proteins on HIV are spaced relatively far apart, limiting the ability of antibodies to attach themselves with both arms. HIV can have as few as 15 spike proteins on their surface. By comparison, an influenza virus has 450 such proteins on its surface which are relatively easy for antibodies to “grab”.
Beyond these attempts to cure the sick, as of mid July, there are 3 vaccines that have been fast tracked into phase three clinical trials–meaning that they are being tested on people, and at least 17 vaccine candidates in phase 1 or 2 trials, which are different stages of testing for safety and efficacy, not to mention a very big pile of other candidates making their way to the pipeline. This large group includes all manner of immunological protection: inactivated virus, protein subunit, RNA, DNA, etc. Vaccines have many hurdles to overcome before they are declared safe and effective, but in the meantime, doctors learn more about how to treat and how not to treat coronavirus everyday. At the very least, for our current pandemic, we seem to be looking and acting in the right direction, which is vastly ahead of where the world population found itself in previous outbreaks.