Vaccines for COVID-19 moving closer

As the world reels from mounting illnesses and deaths due to COVID-19, the race for a safe, effective, long-lasting vaccine to help the body block SARS-CoV-2 is moving forward. The vaccine approaches discussed here were the first to be tested clinically in the United States.

How vaccines induce immunity: The starting line

In 1796, in a pastoral corner of England, and during a far more feudal and ethically less enlightened time, 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 widely believed at the time that once milkmaids became ill with cowpox, a relatively mild disease, they were no longer susceptible to smallpox. The young boy became quite ill, but recovered in about a week. Jenner then injected James with material from a smallpox pustule and observed that nothing untoward 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 that secrete those molecules. Antibodies specifically recognize a shape on a virus or a toxin and bind to it, much like a key that tightly fits into a lock. They can then block 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 to last a very long time, the body has to be tricked into believing it is responding to an infection. When that happens, immune cells called T lymphocytes are activated and can help B lymphocytes make better, long-lived antibodies.

Seeking long-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 instance, 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 such vaccines is not that long-lasting, and several booster shots are needed to enhance immune memory and prolong protection. The injected flu vaccine — a combination of strains of influenza most likely to circulate in a given year — is an example of a killed virus vaccine. Given as a single injection, it only offers protection for about three months. Other killed virus vaccines include those for rabies and the injected polio vaccine; both induce long-lasting immunity only when multiple doses are administered.

Many vaccines are made up of a piece, or a modified version, of the target virus or bacteria. Their effectiveness can vary, and booster shots are generally necessary to achieve relatively long-lasting immunity. For instance, 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. One current vaccine for pneumonia offers protection for four or five years.

Creating vaccines for COVID-19: mRNA and hybrid adenovirus approaches

Unfortunately, research shows not everyone who gets COVID-19 makes natural antibodies against the novel coronavirus. In most people who do, antibody amounts tend to decline. Therefore, natural infection is unlikely to create herd immunity — the slowing of the spread of a pathogen when a large proportion of a community acquires immunity against it. So effective vaccines were desperately needed, and one of them is already being administered in the UK.

There are over 100 different COVID-19 vaccines in various stages of testing and development: preclinical work using animal models, followed by phase 1 (safety), phase 2 (optimal dose, schedule, and proof of concept), and phase 3 (effectiveness, side effects) trials in humans.

Four of many promising vaccines are described below, because these were the earliest to be tested in the United States through clinical trials:

• Vaccines created by Pfizer-BioNTech and Moderna use a type of molecule called messenger RNA (mRNA) that can be mass-manufactured very rapidly. In these vaccines, mRNA induces human cells to make a viral molecule called the spike protein (which in the coronavirus that causes COVID-19 is derived from a protein that studs the surface of the virus and enables it to enter human cells). The vaccines then trigger the immune system to make antibodies against the spike protein. Data released thus far from trials show both vaccines are highly effective, with tolerable side effects. The Pfizer-BioNTech vaccine has passed regulatory approval in Britain and is likely to win emergency use authorization from the FDA in the US this week. The Moderna vaccine will likely receive approval a week later.
• One hybrid vaccine uses a modified, harmless form of a chimpanzee common-cold adenovirus as a capsule, or vector, to deliver the coronavirus spike protein into the body and to stimulate immune response. This platform was developed at the Jenner Institute at Oxford University in collaboration with AstraZeneca. Already in clinical trials in many parts of the world, this vaccine is also currently in clinical trials in the United States.
• Another hybrid vaccine uses a human common-cold adenovirus to deliver the coronavirus spike protein into the body. That platform was developed by Harvard Medical School scientists in collaboration with Johnson and Johnson. This vaccine is expected to complete phase 3 trials in January 2021.

Already, data shared with regulatory agencies has helped establish efficacy and potential side effects for certain vaccines. As COVID-19 vaccines roll out to ever larger circles of people, manufacturers will continue to gather broader data on effectiveness and safety. A central question still to be answered is how long protection might last. Based on information from trials for other diseases, it's likely that hybrid adenovirus vector vaccines will protect individuals for at least one or two years, and probably longer. The levels of antibodies that have been maintained so far for over six months with the mRNA vaccines suggest that these vaccines are likely to sustain antibody levels for about as long as the hybrid vaccines.

Months ago, many of us wondered when an effective vaccine would be widely available. Now one of these vaccines has already been given to recipients in the UK. In the US, immunizations will likely begin during the last two weeks of December 2020.

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For additional information on COVID-19 vaccines, see the Harvard Health Coronavirus Resource Center.