I began these whole series of lectures by pointing out that the best way to deal with diseases is not to get them in the first place. I pointed out that most of the differences in mortality between developed and undeveloped nations can be accounted for by differences in the availability of clean water, nutritious food, and vaccination. Today we begin looking at the specifics of how vaccination and related immune therapies protect people. Before we begin, I'm going to give a tribute to two heroes in the fight for public health, Dr. Carlo Urbani and Dr. Li Wenliang died of newly evolved strains of Coronavirus, SARS and COVID-19 respectively. Both these men died caring for patients at the beginning of different epidemics at a time when we were just beginning to understand the seriousness of the threat from a variant of a virus that ordinarily causes nothing more than a really bad cold. To remind you, nature is the world's worst bio-terrorist. The best way to honor these men and the others who have made such sacrifices is to maintain our vigilance and preparation and improve the nimbleness and effectiveness of our technology. There are two very different strategies in harnessing the power of the immune system to fight off infections. The first or passive immunization delivers antibodies developed from one immune source to protect another vulnerable individual. That is, you give an immune challenge to some individual, the donor, you collect antibodies that the donor makes and you pass them on to the person to be protected, which of course now will attach to whatever the pathogen is, then hopefully tie it up and make it less of a threat. The other strategy, active immunity, challenges the person directly. That is, the person to be protected makes his or her own antibodies, possibly T-cells, memory cells, and essentially provides his or her own protection against the pathogen. Passive transfer can occur naturally as we discussed in Course 3. We discussed the importance of maternal antibodies and colostrum and in breast milk in the lecture on tolerance and also discussed protecting the infant with maternal antibodies in the blood. Later, when we looked at type two hypersensitivity, we looked at a situation of pathology, erythroblastosis fetalis where the transferred antibodies attack the fetal red blood cells. But what we really want is to harness the ability to transfer antibodies from one person to another to help keep people alive. These techniques were pioneered in the late 1800s by Shibasaburo Kitasato and Emil von Behring in developing Sera to be used against diphtheria and anthrax. First they showed you could protect mice from tetanus with antibodies and then they used these techniques to develop Sera that would protect human beings. At this time doctors occasionally used something that we currently call Convalescent Plasma Therapy as well. This is a fairly primitive technique in which a doctor simply transfuses whole blood or plasma directly from someone who's recently recovered from an infection into someone who is currently seriously ill. This has been used as a desperation strategy even in the 21st century on Ebola patients and on COVID-19 patients and with some success. You can also improve this by using plasmapheresis, which we again discussed in the previous course, to extract and concentrate the antibodies from the serum. Blood serum containing antibodies has been used in clinical practice from the early decades of 1900 up until World War II, after which antibiotics became the standard of treatment. In this picture you see a young child being administered horse antibodies. Horses were used to produce it and are still used to produce some antivenom antibodies today. The antibodies this team is administering to this child are there to tie up a diphtheria toxin. This is an exotoxin that is secreted by the bacteria. It poisons cells by blocking their protein synthesis and of course then when they die, the bacteria can use them as a food source. That's clearly not something we want. This was, as I said, a standard of care, and when diphtheria broke out in Anchorage, the serum had to be sent in by dog sled. Here is a photograph of the lead dog Balto, with Gunnar Kaasen his musher. Gunnar gave much of the credit for their successful arrival to Balto's ability to sense dangerous territory and guide the sled to safety. Today, the Iditarod honors the relay that brought the serum to Anchorage in the middle of the diphtheria epidemic and there is a statue of Balto that graces Central Park in New York City. Even with the advent of antibiotics, antibody therapy has still remained the standard of care in a number of clinical situations. Someone might be immunodeficient. You can't vaccinate somebody successfully if they're immunodeficient. Also there are cases where you have had very young infants exposed to diseases. There have been two cases in recent years where children of anti-vax parents with measles were found wandering around maternity wards in two different hospitals. In this case, the babies were way too young to be vaccinated and were given anti-measles antibodies to protect them. If a patient is exposed to a disease and even if that patient has been treated with antibiotics or has already been vaccinated against the disease, sometimes you also administer antibodies to tie up any bacterial toxins that may be produced before you can get rid of the bacteria. This is done for tetanus and it's sometimes done with anthrax infections as well, and the inactivation of venoms. Whether it's snake venom or insect venom or any other venom, most of these are proteins that do damage to the body and they can be tied up with antibodies, and we do still produce many of these anti-venoms by using horses. The development of antibody treatment to be used in various therapies is actually a rapidly moving field, so I'm probably going to be missing some things and I'm going to give you a few examples. Antibodies may just be the best way to treat viral diseases period. In terms of something like Ebola, we have tried a number of antibody therapies, and currently, we have a two-antibody therapy that seems to be very successful especially if it's administered early. In the case of Zika, there is ongoing work using antibodies to protect embryos. This is currently being done with mice, but there is no reason why this shouldn't turn into an effective therapy for mothers who are infected and want to make sure that their babies are not compromised. As multi-drug resistant strength of bacteria become more prevalent, this may be one of the few acute and effective therapies available and finally, we are using antibodies to treat various forms of cancer. Some of the newest therapeutic agents in cancer therapy are monoclonal antibodies that attach to growth factors over their receptors. They preferentially target cancers because in so many cases, cancers up-regulate the production or sensitivity to such signals, and we're going to revisit this in the last lecture of the course. Finally, let's look at some practical considerations. Antibody therapies or passive immunization have a big advantage over just about everything else and that is protection is immediate. You slap those antibodies into somebody, they will go and tie up anything that you're trying to tie up and it happens quite quickly. However, there are disadvantages. In the short term, they work very well, but they wear off after a couple of weeks. So they're temporary and you don't get memory cells. It's something that you do and then it's over. Also, if you have to therefore repeat the administration of antibodies, that can lead to something called serum sickness because you actually can't get immune to the antibodies that you're putting in to help you become immune to your illness. This is the basis of some of the ELISA assays we looked at. So serum sickness, which is a type III hypersensitivity, can lead to all kinds of damage and we currently try to avoid this by making what we call humanized antibodies. That is we engineer the monoclonal antibodies to be as similar to human ones as possible, thus making it less likely you will become immune to them after repeated treatments. The last thing I have to say is that this is a really expensive form of therapy. It's much more expensive to develop and deliver this protection. Antibiotics, when you can use them are much cheaper. Even vaccines which are expensive to develop, once you've developed and manufactured them, they're much cheaper as well. Now, not that all vaccines are cheap to develop. Of course, what we really need is a traditional vaccine. Vaccines prevent you from getting sick in the first place. Vaccines are expensive to develop, but once you've developed and manufactured them, they're much cheaper as well. Because this is supposed to be a biology course and not a political or an economics course, we don't spend a lot of time on issues of developing, manufacturing, and delivering vaccines. But these issues often provide the highest barriers to achieving decent public health, and many of the technical issues we look at involve fixes for avoiding such problems. So let's look at the immunological principles in vaccine development.
