As the world recovers from illnesses and deaths from COVID-19, the race is on for a safe, effective and long-lasting vaccine to help the body block the novel coronavirus SARS-CoV-2. The three vaccine approaches discussed here are among the first to be clinically tested in the United States.
How vaccines induce immunity: the starting line
In 1796, in a pastoral corner of England, and in a much more feudal and ethically less enlightened era, Edward Jenner, an English country surgeon, inoculated James Phipps, his gardener’s eight-year-old son, with cowpox pustules obtained from the arm. of a milkmaid. It was generally believed at the time that once dairy women got smallpox, a relatively mild disease, they were no longer susceptible to smallpox. The young boy fell very ill, but recovered in about a week. Jenner then injected James with material from a smallpox pustule and observed that nothing untoward had happened. A new scientific approach to disease prevention was born.
A century later, it became clear that vaccination – a term Jenner coined from the Latin name for cowpox, Vaccinae variolae – worked because vaccines induce protective immune responses. We now know that vaccines can generate neutralizing antibodies by activating immune cells called B lymphocytes which secrete these molecules. Antibodies specifically recognize and bind to a shape on a virus or toxin, much like a key that fits tightly into a lock. They can then prevent the virus or toxin from binding to our own cells, effectively disarming it.
However, in order for these antibodies to bind strongly to viruses or bacteria and last a very long time, the body must be tricked into believing that it is responding to an infection. When this happens, immune cells called T cells are activated and can help B cells make better, long-lived antibodies.
Seeking lasting immunity: fragments and targets
Many weakened (attenuated) live viruses have been used as vaccines. These tend to provide long-lasting immunity even after a single dose. The yellow fever vaccine, for example, generates immunity that can last a lifetime. Other examples include measles, mumps and rubella combined (MMR), rotavirus, smallpox, and chickenpox vaccines.
Some vaccines are just killed versions of the whole virus. Immunity in response to these vaccines is not that long lasting, and several booster shots are needed to improve immune memory and prolong protection. The injected influenza vaccine – a combination of influenza strains most likely to circulate in a given year – is an example of a killed virus vaccine. Given as a single injection, it only provides protection for about three months. Other killed virus vaccines include those against rabies and injected polio vaccine; both induce long lasting immunity only when multiple doses are administered.
Many vaccines are made from a piece, or a modified version, of the target virus or bacteria. Their effectiveness can vary, and booster shots are usually needed to achieve relatively long-lasting immunity. For example, the modified versions of the toxins released by the bacteria that cause tetanus and diphtheria given in the Td vaccine can generate protection for about 10 years. A current pneumonia vaccine provides protection for four or five years.
Creation of vaccines for COVID-19: mRNA and hybrid approaches
Unfortunately, research shows that not all patients with COVID-19 make natural antibodies against the new coronavirus. Even in those who do, the amounts of antibodies tend to decrease about two months after the initial diagnosis. Therefore, natural infection is unlikely to create herd immunity (the slowing down of the spread of a pathogen when a large part of a community acquires immunity to it). Effective vaccines are therefore desperately needed.
There are over 100 different COVID-19 vaccines at different stages of testing and development: preclinical work using animal models, monitoring phase 1 (safety), phase 2 (optimal dose, schedule and proof of concept) and phase 3 (efficacy, side effects) in humans.
Three promising vaccines (there are many more) are discussed below, as they will be the first to be tested in the United States in clinical trials:
- A vaccine created by Moderna in Cambridge, Massachusetts, uses a type of molecule called messenger RNA (mRNA) which can be mass-produced very quickly. In this vaccine, mRNA induces human cells to make a molecule called a spike protein, which nails the surface of the coronavirus and allows it to enter human cells. The vaccine then prompts the immune system to make antibodies against the spike protein. Phase 1 human trials were launched in March 2020 by the NIH. The first results showed that the vaccine is safe and generates high levels of neutralizing antibodies. The vaccine is expected to enter phase 3 clinical trials in July 2020.
- A hybrid vaccine uses a modified, harmless form of a chimpanzee cold adenovirus as a capsule, or vector, to deliver the coronavirus spike protein into the body and to stimulate the immune response. This platform was developed at the Jenner Institute of the University of Oxford in collaboration with AstraZeneca. Already undergoing clinical trials in many parts of the world, this vaccine is expected to enter clinical trials in the United States in August 2020.
- Another hybrid vaccine uses a human cold adenovirus to deliver the coronavirus spike protein into the body. This platform was developed by scientists at Harvard Medical School in collaboration with Johnson and Johnson. This vaccine is expected to enter phase 1 clinical trials in September 2020.
In animal models, all three vaccines confer protective immunity against SARS-CoV-2. Future trials will help establish their long-term effectiveness and potential side effects. A central question will be how long the protection could last. Based on information from trials for other diseases, it is likely that hybrid adenovirus vector vaccines will protect individuals for at least one or two years, and possibly longer.
Many wonder when a vaccine will be available. If all goes well with at least one of these candidate vaccines, it may be as early as the first quarter of 2021. Much depends on the results of the larger trials that will continue this summer.
Join researchers and medical scientists at @MassCPR for an update on the status of COVID-19 vaccine development, with a focus on ongoing human vaccine trials and more to be launched soon. To register for this event, click on here.
For more information on the coronavirus and COVID-19, see the Coronavirus Resource Center at Harvard Health Publishing.
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