Coping with the COVID-19 Pandemic
At the beginning of a pandemic caused by a novel virus, there is not enough time to develop new drugs specific to this virus. Trying to save patients’ lives, doctors repurpose drugs approved for other diseases or viral infections, hoping that they will work. This is a good strategy since these drugs are known to be safe, and their side effects are known. During the COVID-19 pandemic many such therapeutic strategies were tested.
The pharmaceutical company Gilead has expertise in viral polymerase inhibitors, having successfully developed such drugs for Hep C. They had previously repurposed a polymerase inhibitor that was originally developed for Hep C to treat Ebola infections. This drug, remdesivir, had been tested in humans in Africa and was established to be a safe and promising therapeutic. However, when Regeneron’s antibody treatment for Ebola proved to be more efficacious, remdesivir’s development was halted before it was approved for use.
In 2020, Gilead quickly tested remdesivir for efficacy in inhibiting the polymerase of SARS-CoV-2. It was found to inhibit virus replication both in animals and in human cells in test tubes. Gilead rushed to perform clinical trials with the drug and also began to provide it on a compassionate use basis. When the drug appeared to shorten the course of disease, the US Food and Drug Administration granted Emergency Use Authorization for treating severely ill patients. The drug requires intravenous administration and causes some side effects, limiting its use to the severely ill.
Dexamethasone is a steroid that has long been used to treat arthritis, acute respiratory distress, and other conditions. A British clinical trial has shown that use of this drug reduces the death rate of COVID-19 patients who were on ventilators by a third, and by 20 percent for those on external oxygen support. This is a good example of a drug that has been repurposed for treating acutely ill patients during a pandemic.
As we described earlier, another approach being pursued to treat COVID-19, is taking plasma from those who have recovered from the infection and injecting it into sick patients. As each individual is different and could mount a different kind of antibody response, there could be high variability in the efficacy of antibodies obtained from different donors. Several companies are developing potent neutralizing antibodies that can be administered to patients, which will eliminate this complication.
Two types of interferons are approved as drugs for the treatment of Hepatitis B and Hep C infections, as well as for the autoimmune disease multiple sclerosis. There are data to suggest that SARS-CoV-2 has a gene that functions specifically to block the production of interferon, so it may be a good strategy to consider interferon treatment. The usefulness of the two approved forms of interferon for COVID-19 has yet to be established. Also, these drugs are expensive, need to be injected into patients, and have significant side effects, which hinders their use at large scale.
Quinine is a medication isolated from a tree bark that has been used for the treatment of malaria for almost 400 years. Because of its bitter taste, the British mixed it with gin to create the popular drink known as gin and tonic. Great efforts were made in the 1930s to make analogs of quinine that could be synthesized in the laboratory. This led to the discovery of chloroquine and, later, hydroxychloroquine by chemists at the German company Bayer. At the end of World War II, US troops captured the drug, and in 1947 it was found to be effective in preventing transmission of malaria. The drug was also repurposed to treat some autoimmune diseases. Although it has been used for so long, we still do not really understand how this drug works. The excitement about it possibly being able to treat COVID-19 reflects the paucity of available treatments. Only carefully controlled clinical trials can determine whether drugs might be effective in controlling the virus. Current data suggest that hydroxychloroquine is not an effective treatment for COVID-19.
Inhibiting a Cytokine Storm
As we described in chapter 4, sometimes an overexuberant immune system can cause severe disease. This can arise due to either extensive spread of the virus, which elicits too strong an immune response, or a faulty immune system. An overly active immune response can lead to the production of large amounts of cytokines, a so-called cytokine storm. Dramatic effects result, including acute inflammation, a precipitous drop in blood pressure, and uncontrolled blood clotting throughout the body. The major cytokines that are secreted during a cytokine storm are called IL6, TNF, and IL1. Drugs that block the action of these cytokines are already approved for the treatment of a variety of autoimmune diseases. If cytokine storms are the cause of death in the most severely ill patients, identifying which patients could benefit from cytokine blockade and which cytokines are important to block could play a role in reducing the mortality of COVID-19.
The Future of Antiviral Drugs
Developing efficacious antiviral drugs is a time-consuming and expensive proposition. Identifying a good drug candidate is very hard. But this is just one step in the process, as expensive clinical trials are needed to establish that a drug candidate is safe and efficacious. This, in turn, requires optimizing the dose to be used and the method of administering the drug. The majority of drugs that are developed fail to get approved. For infectious diseases that are likely to continue to afflict us for a while, such as those caused by HIV, Hep B, Ebola, and influenza, companies continue to devote effort and expense to develop good therapies. To prepare adequately for potential pandemics, we will need a different model for developing antiviral drugs. These models will be predicated on new scientific advances and approaches, and will be facilitated by public-private partnerships. We will opine on these issues in the epilogue.
The most effective strategy to end the scourge of an infectious disease– causing virus is to develop a vaccine that protects against it. That is the topic of the next chapter.
7 Vaccines
Human history is inextricably linked with the pain inflicted on us by infectious disease-causing microbes. Until relatively recently, most families would lose at least one child to infectious diseases. Smallpox killed hundreds of millions of people in the twentieth century alone. In present times, especially in the developed world, it is hard to imagine this kind of trauma so common even 100 years ago. A large part of the reason that this situation has changed is the development of vaccines that can protect us from infection and disease. Indeed, vaccination has saved more lives than any other medical procedure. Comprehensive smallpox vaccination programs have saved hundreds of millions of lives and led to its eradication from the planet. Vaccination has also almost eradicated polio and is a major reason for the dramatic decline in childhood mortality.
As we discussed in the chapter on pandemic mitigation, infectious disease–causing viruses stop spreading in a population when the proportion of the population that becomes immune to the disease rises above a threshold. For highly infectious viruses, this threshold is very high. So, it is difficult to acquire herd immunity naturally without many people being infected, which can take a long time and potentially cause many deaths. Vaccination allows a population to acquire herd immunity rapidly. Vaccination protects not just the immunized person but the whole community, including the most vulnerable members of society, such as the elderly and immunocompromised.
We began this book by describing Edward Jenner’s invention of a safe smallpox vaccine. In this chapter, we will describe how vaccination has evolved since the time of Jenner and Pasteur, and how modern technologies are addressing the challenge of producing a COVID-19 vaccine.
How Vaccines Work
In the chapter on immunity you saw that, upon infection, the immune system mounts a multipronged response aimed at eradicating the virus from the body. The first responders are the cells of the innate immune system, which try to control virus replication and fence in the virus near the site of infection. These cells secrete cytokines that make the environment inhospitable for the virus. Phagocytic cells also eat up the virus and carry them to lymph nodes. Here, B and T cells of the adaptive immune system interact with the
virus’s proteins, and subsequently an immune response tailored to the infecting virus is produced. There are two arms of this response. One arm is comprised of antibodies that bind to the spike proteins of the virus and thus prevent the virus from entering our cells and infecting them. The second arm is comprised of T cells. Killer T cells detect specific fragments of the virus’s proteins that bind to our HLA proteins. These HLA-bound protein fragments are displayed on infected cells. Upon detecting a viral protein fragment, killer T cells secrete products that punch holes in the infected cells and kill them. We mentioned in the chapter on immunity that there are other subtypes of T cells that have diverse functions. One of these subtypes, called a “helper” T cell, helps mediate the Darwinian evolutionary process that leads to the production of potent antibodies. After an infection is cleared, antibodies and memory T cells and B cells specific for the infecting virus circulate in the body. These products of adaptive immunity can mount rapid and robust responses when needed, thus protecting against reinfection, at least for some time.
The goal of vaccination is to stimulate the immune system to produce antibodies and memory T cells and B cells that attack the specific virus from which we wish to protect the population. Moreover, vaccines aim to stimulate antibody and memory immune responses that are durable for a long time, ideally for the lifetime of the individual. All of this has to be achieved in a way that is safe so that vaccination does not result in a full-blown form of the disease or lead to any other adverse effects. While minimizing, or preferably eliminating, side effects is an important consideration for the development of any therapeutic, this is especially important for prophylactic vaccines as they are administered to healthy people.
The vaccine must contain the virus’s proteins, either in whole or in part. Otherwise antibody responses specific to its spike protein or T cell responses to fragments of this specific virus’s proteins will not be elicited. All effective prophylactic vaccines induce potent antibody responses. Antibodies prevent the virus from infecting cells, which in turn prevents the virus from multiplying. Vaccines may also need to elicit T cell responses. One of the most successful vaccines protects against infection by the virus that causes yellow fever. This virus was a major health hazard for decades. The deaths of French soldiers due to yellow fever was one of the reasons France sold their North American holdings to the United States in 1803 (the Louisiana Purchase). The yellow fever vaccine developed in the 1930s elicits antibodies and potent and long-lived killer T cell responses. Yellow fever is still endemic in parts of Africa and South America.
From the chapter on immunity, you may recall Janeway talking about the immunologists’ “dirty little secret.” That is, without a proper innate immune response, there is no adaptive immunity. This means that an effective vaccine must also induce a potent innate immune response. We do not understand innate immunity as well as we do adaptive immunity. Even for the latter, we do not really know what factors lead to durable memory responses and antibodies that offer protection for a long time. It is also important that memory T cells are localized to, or can quickly get to, portals in our body through which a particular virus enters us, as this would quickly terminate infection. We do not know much about how to achieve this goal either. So, vaccine development remains a somewhat empirical process. Many approaches are tried, and some strategies work better than others in different applications. Let’s discuss some of these approaches to vaccine design.
Types of Vaccines
Live Attenuated Vaccines
Live attenuated vaccines are composed of the real virus that causes the disease. But the virus used in the vaccine is one that has been weakened (attenuated) so that it does not cause the full-blown disease. When people are immunized with these vaccines, the virus in the vaccine infects cells and multiplies, thus generating an immune response.
The smallpox vaccines described in chapter 1 were “live” vaccines. In the process of variolation, the pus that was collected from patients contained the live virus. You may remember that this material was dried and stored for a while before it was administered by an “experienced person.” The drying and storage likely damaged the virus sufficiently so as to usually not cause full-blown disease. The “experienced person” probably knew how much of this material to administer so that it was safe. But variolation was a dangerous procedure and sometimes caused smallpox outbreaks. Jenner also used a live virus, but it was the cowpox virus. Viruses that infect animals usually do not thrive in humans because these viruses have adapted to infecting and multiplying in animals, and we are different. Jenner’s vaccine was safe because it was a virus from an animal. It was efficacious because the proteins of cowpox and smallpox viruses are similar, and so antibody and T cell responses that developed upon vaccination with the cowpox virus were also specific for parts of the smallpox virus.
Recall that Pasteur serendipitously made a big advance toward the creation of safe live attenuated vaccines with his chicken cholera vaccine. He then took this a step further with his rabies vaccine. Animal viruses that are not adapted to multiply well in us can jump to humans when they acquire the right mutations or when the right kinds of recombination of different viruses occur. While it is unclear whether they knew anything about all this, to weaken the virus, Pasteur and his collaborator, Roux, turned this fact on its head. They took the virus that afflicted dogs and humans, and repeatedly infected rabbits with it. Sequentially passaging the virus through rabbits in this manner likely led to the virus adapting to multiply better in rabbits, making it less lethal for humans. The rabies virus infects the spinal cord; to weaken the virus further, Pasteur and Roux air-dried spinal cords from infected rabbits and used the strains thus derived in their vaccine.
Human viruses can also be weakened by growing them in cells in the laboratory. As mutations emerge, the ones that multiply best in these cells take over the population. These viruses are likely to not multiply as well in humans because they are no longer optimized to thrive in an environment that includes human immunity. Thus, they may be suitable for use as live attenuated vaccines. Different approaches continue to be developed to attenuate viruses so that they can be used as vaccines.
Weakened or live attenuated viral vaccines, while effective, can still sometimes cause the full-blown disease associated with natural infection. This risk motivated the search for vaccines that are not composed of a live replicating virus.
Killed or Inactivated Vaccines
In the late nineteenth century, two groups of scientists, in the United States and in France, showed that killed bacteria could be effective vaccines. The killed or inactivated microbes cannot replicate in humans anymore, and therefore they cannot cause disease. This is accomplished by treating the microbes with various chemicals or subjecting them to high temperatures. One chemical that has been used for this purpose is formaldehyde, which is used for embalming the deceased. Inactivating a microbe using such a chemical has to be done carefully. Using too little formaldehyde will not kill the microbe, and using too much will overly damage it. An intact microbe is required because otherwise vaccination with it will not elicit immune responses to the microbe’s proteins in the way in which they are displayed on the real virus. For example, if the inactivation procedure alters the way that the spike protein is displayed, the vaccine will not be able to elicit antibodies that bind to the spike protein of the real virus. Thus, the vaccine-induced antibodies would not be effective in preventing infection.
For reasons that are not entirely clear, inactivated vaccines elicit weaker immune responses than live vaccines. So, inactivated virus vaccines often require a “booster shot.” By administering the same vaccine again, the memory B cells and T cells generated during the first vaccination get reactivated and multiply. The potency of the antibodies can also increase.
Subunit Vaccines
In the chapter on antiviral therapies, we described how recombinant DNA technology created the modern biotechnology industry. The gene encoding information about a
single protein could be isolated and then inserted into another DNA fragment, and the protein could be produced by growing it in cells. With the advent of these methods, scientists started thinking about how this technology could be used to make safer vaccines. Since antibodies and T cells target only parts of viral proteins, it seemed logical to use recombinant DNA technology to produce a few viral proteins in large quantities and use these proteins as the vaccine. These so-called subunit vaccines would obviously be safe, as they do not contain the virus at all, just some of its proteins. These vaccines would also be much simpler and easier to manufacture compared with the laborious processes associated with growing viruses or inactivating them just right.
A vaccine that protects against hepatitis B infection was one of the first ones made using recombinant DNA technology. Hepatitis B is a virus that infects the liver and is a major cause of liver cancer and liver failure around the world. Most people’s immune systems can clear the infection, but some cannot, and they become chronically infected. About 3.5 percent of the world’s population is living with chronic hepatitis B infection. Chronically infected persons can spread the virus to others who come in contact with their blood. Infants born to infected mothers can also be infected.
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