Читать книгу Viruses: More Friends Than Foes (Revised Edition) - Karin Moelling - Страница 23

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 long, which is bigger than that of many other viruses. During replication viruses make mistakes — that is, they introduce wrong nucleotides, leading to mutations. The large CoV-2 genomes could accumulate too many mistakes and die out. This is prevented by a correction system, a “viral proof-reading”, to eliminate mistakes. This leads to a genome stabler than that of many other viruses. Mistakes, meaning mutations, are normally a means by which a virus evades the immune system of the host, escaping by making rapid changes. Mutations of CoV-2 have been observed, as expected, with numerous viral isolates being sequenced. Some of them are leading to a much higher pathogenicity. Problems for vaccines will have to be determined.

Another approach is already under investigation. It was tried during an Ebola virus outbreak on an American who returned to the USA infected by this deadly virus, of which more than 90% of infected people do not survive. The survivors are carriers of antibodies, and these were isolated from their blood in an attempt to cure newly infected people. The patient survived. This approach is being used with the antibodies of COVID-19 survivors. It cannot save the whole world.

The efforts to develop vaccines or drugs have activated hundreds of researchers in many fields: virologists, molecular biologists, biochemists, chemists, geneticists, molecular designers and bioinformatics specialists. This is going to be exciting. Start-up companies are usually innovative and original. Then the big pharmaceutical companies will need to step in. They will have to drive the approach to the market, which requires more resources than small start-up companies have. We will need highly up-scaled production for worldwide supplies and distribution. This will take time, however.

We need an immediate intermediate solution.