Viruses: More Friends Than Foes (Revised Edition). Karin Moelling
two weeks after recovery. Normally such antibodies are thought to protect the carrier from a reinfection, if they are strong enough. The view has been propounded that people do not have any antibodies against this novel virus, as our immune systems have never encountered it. This may not quite be so, since the four seasonal coronaviruses, appearing regularly in winter, may cross-react. Recently some data have indicated that 15% to 20% of the population in certain regions such as New York City have antibodies, some of them without having been sick — which leads to the question of whether they were infected with the new virus without knowing it or whether previous infections may have contributed to this result. This will be tested on a large scale. The total number of infected people plays a part in determining the number of protected people.
Could antibodies be too weak to afford protection? Or too short-lived? Could they even do harm? There are indeed opposite reactions known for some viruses, which can enhance the disease upon reinfection. This is designated as antibody-dependent enhancement (ADE) and is known for Dengue viruses. It is rare and may hopefully not apply to CoV-2, but is very relevant for forthcoming immunizations. Do vaccines protect against infections, and are they safe?
Before vaccines become available, antibody tests would be very useful — quick tests with immediate answers. Then people could travel, teach children and go to work without any risk. However, these tests are simple and sometimes not quite exact enough and need to be correctly done. The rate of false results can be limiting for commercial approval. Some such tests have already entered the market.
Herd immunization
An internationally accepted measure against the spreading of CoV-2 is isolation of people, social distancing. A disadvantage of this is that it results in a low rate of infection of the population and lack of healthy recovered antibody carriers. They are important to keep the reproduction number R0 below one. Then each person infects fewer than one new person. There are calculations that about 66% of the population needs to have antibodies to bring the epidemic to a halt (based on an assumption that R0 equals 3).
Another risk is that the virus only “hides” and comes back when measures are relaxed. With no vaccine available as yet, the way to increase immunization is the old-fashioned virological procedure called herd immunization. This is often misinterpreted: It is not a prescribed procedure, it just happens, preferentially among younger people who do not become as sick as the elderly. This may also be the only way in which tropical or low-income countries with areas of high population density can cope with the pandemic — or in refugee camps, where many people are young. There may, however, be other risk factors for young persons, such as tuberculosis, HIV, diabetes, or pollution effects. However, without western-style medical help and hygiene, this may be the only possible response. It may work out better than we fear. This approach is being taken by Sweden — where, however, the population density is very low, and Swedes were instructed to keep at a distance from one another. Boris Johnson intended to adopt this approach in the UK, but was attacked and he took it back. From theoretical calculations such a procedure would result in a high peak of infections but a lower chance of a second or third peak. But the number of deaths may be up to twice as high, as shown in previous studies with influenza.
A politician has to decide between two extremes: save as many lives as possible, as is done in Europe, or keep the economy up — an option first tried by President Trump in the USA. However, when he was told by his medical adviser Toni Fauci from the National Institute of Allergy and Infectious Diseases, that his approach might cost a million deaths, he modified it. Decisions on how to cope with the pandemic range somewhere between these two extreme options.
We do not know, whether the social distancing in many European countries prevented a herd immunization among the less endangered middle-aged population. The exit strategies may take over.
Vaccination
Eradication of viruses by a vaccine has been successful in the past, only in some very spectacular cases, but it always required enormous effort. Vaccination against polio was a big success and involved an annual worldwide Polio Vaccine Day, for which even wars were interrupted. Some infections still pop up occasionally. Smallpox vaccine was probably one of the mankind’s greatest successes in medicine. Only the elderly still have the two scars on their upper arms from the vaccination during childhood. There are successful vaccines against measles, even though some people always are against it. The vaccine against Influenza is redesigned every year, because the genetic composition of the virus changes. It normally comprises several virus strains. Even if they are not predicted completely correctly, the vaccine reduces the severity of the disease. There are international surveillance systems, which help to predict the best composition for the Influenza vaccine for the coming season. It takes 6 months to prepare enough vaccine for each season. There is so far no vaccine against HIV because of its high mutation rate. However, HIV can be treated with combinations of drugs, of which more than 30 are available. HIV is unique in that respect.
Vaccine preparations against CoV-2 for the whole world will take time and will involve production on an unprecedentedly large scale. Even before a vaccine has become available, Bill Gates initiated large-scale production.
Dozens of start-up companies have begun with vaccine development. Various approaches are possible. This is important, as we do not know whether a strong or a weak immune response is best. One type of experimental vaccine uses inactivated virus — which is the old-fashioned way of making a vaccine. Yet massive virus production for inactivation may present a risk, and nothing is 100% reliable — including the inactivation protocol!
Alternatively, only viral subunits are prepared: mainly the spike, the surface protein, because antibodies against this region are likely to neutralize the incoming virus and prevent its infection of host cells, making it unable to replicate. New on the scene are genetic vaccines. These can be designed from the genome sequence and synthesized within days. Again, the spike is the preferred sequence. The vaccine is composed of either synthetic viral RNA or DNA. RNA can also be expressed from synthetic DNA plasmids and produced on a large scale. RNA vaccines have not been used before in treating animals or people. However, they were given express approval as “investigational new vaccines” by several health authorities. To accelerate their development, the necessary cell-culture experiments are being performed in parallel with, rather than in advance of, the human clinical trials. DNA vaccine has been used for 30 years, and there are vaccines against HIV envelope regions combined with immunogenic regions of the virus which are genetically more stable. I was involved in the design of such a vaccine and some Phase I/II studies on patients in Zurich. The US military is still using this genetic vaccine, supplemented with adjuvants.
In Zurich we also designed a “naked DNA” agent against tumors, by expressing a cytokine to treat a cancer, malignant melanoma, by Interleukin IL-12. As required, we tested the treatment in two animal models beforehand, mice and white horses (which also develop malignant melanomas), and then in 12 patients, with some success. The “vaccines” are produced by the person treated, first by making a protein — a viral antigen — and then the antibodies against it. The amount of antibodies produced from DNA were low but long-lasting in our studies. The way from RNA to protein is one step shorter than from DNA to protein, and works directly in the cytoplasm. Thus RNA may be superior. Several genetic vaccines are the first experimental vaccines currently under investigation.
Alternatively, artificial viruses can be fabricated by genetic engineering techniques and administered as liposomes, virus-like particles, or harmless viruses as carriers of CoV-2 surface proteins. One vaccine is based on the old-fashioned smallpox virus vaccine, which proved to be very safe, the MVA (Modified vaccinia-virus Ankara) enriched by the CoV-2 envelope protein. Also, the bullet-shaped vesicular stomatitis virus, VSV, has been genetically engineered to carry the spike protein as a vaccine. Similarly, Adeno-Associated Virus (AAV) is developed into a vaccine.
Coronaviruses are expected to allow the design of a vaccine, because they do not change by so many mutations as most other RNA viruses do. The CoV-2 genome is 30,000 bases