Merck Manual

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Commentary: Update on COVID-19 Vaccines

1/11/2021 Matthew E Levison, MD, Adjunct Professor of Medicine, Drexel University College of Medicine

As of mid-December 2020, The New York Times Coronavirus Vaccine Tracker listed 59 vaccines in clinical trials in humans, 16 of which have reached the final stages (phase 3) of testing. At least 86 additional vaccines are under active investigation in animals ( SARS-CoV-2 vaccines are based on several different technologies, which determine vaccine attributes, such as the number of doses, stability at room temperature, speed of development, scalability, need for adjuvants (vaccine additives), and cost.


What are the COVID-19 vaccine types?

The vaccines against SARS-CoV-2, the virus that causes COVID-19, can be classified into two broad categories:

  • Gene-based
  • Protein-based


Gene-based vaccines include RNA, DNA, virus vector, and live, weakened (attenuated) SARS-CoV-2 virus vaccines.

Protein-based vaccines include inactivated SARS-CoV-2 virus and viral protein or protein fragment (subunit) vaccines.

Most of these vaccines teach the immune system to recognize and attack the spike protein, which studs the surface of the SARS-CoV-2 virus and lets it bind to the host cell.

mRNA vaccines: SARS-CoV-2 is an RNA virus, having RNA (ribonucleic acid) as its genetic material. Several COVID-19 vaccines use an artificial fragment (in the form of messenger RNA or mRNA) of the gene that encodes the spike protein. This mRNA gene fragment is coated with a thin layer of fatty material (lipid) that allows the gene to enter the vaccine recipient’s cells. The recipient’s cells then use this artificial gene to synthesize the spike protein, which then stimulates a protective immune response. Two doses spaced 3 or 4 weeks apart are required. Two mRNA vaccines, now given emergency use authorization by the regulatory authorities in the United States, are currently being used to vaccinate people in multiple countries.

DNA vaccines: One SARS-CoV-2 vaccine uses a similar gene fragment but in this case a piece of DNA encodes the spike protein. These DNA pieces are introduced directly into the vaccine recipient’s cells. The recipient’s cells then produce the spike protein.

Viral vector vaccines: In viral vector vaccines, the SARS-CoV-2 spike protein gene is inserted into a harmless carrier virus that delivers the gene to the vaccine recipient’s cells, which in turn read the gene and assemble the spike protein as if it were one of their own proteins. The spike protein is presented on the surfaces of the recipient’s cells, provoking an immune response. The most common viral vectors are non-replicating human adenoviruses that are further weakened so they cannot cause any disease.

Live, attenuated SARS-CoV-2 vaccines: Another type of vaccine consists of live, attenuated (weakened) SARS-CoV-2. The virus is still infectious and can cause an immune response. With some live, attenuated vaccines, such as the Sabin oral poliovirus vaccine, there is a remote possibility that the weakened virus could revert back to its full virulence and cause disease. It is not known whether this reversion will occur with the live, attenuated SARS-CoV-2 vaccine.

Inactivated SARS-CoV-2 vaccines: These vaccines use SARS-CoV-2 virus that has been inactivated with heat, radiation, or chemicals, which completely stop the virus’s ability to replicate.

Protein-based vaccines: These vaccines contain SARS-CoV-2 proteins or protein fragments (subunits) that stimulate a protective immune response. Adjuvants, which are vaccine additives, are required to enhance the magnitude and durability of antibody response.

Noninjectable investigational vaccines: All the previously discussed vaccine types are given by injection. Other routes of vaccine administration are also undergoing evaluation, including a nasal spray and an inhaled vaccine (like from an asthma inhaler). By duplicating how the wild virus attacks, these vaccines might be better at stimulating local immunity on the mucosal surfaces of the respiratory tract.


Is one dose of COVID-19 vaccine enough?

Many traditional childhood vaccines require a second dose, known as a booster, several weeks or with some vaccines, even years later. The booster dose strengthens immunological response and memory.

The current FDA-approved vaccines are given in two doses 3 or 4 weeks apart. A single injection of either of these two-dose vaccines does provide protection against COVID-19 but not as much as 2 doses, and we do not know how long that protection lasts. Note that several other vaccines still in the testing phase are designed to be given as a single dose, but efficacy data are pending.

Doctors do not know what the immune response and safety would be if two different COVID-19 vaccines were used for the first and second dose, so currently they recommend people get the same vaccine for the second dose.


Will spike protein mutations weaken vaccine efficacy?

Viruses constantly mutate. On average, a SARS-CoV-2 virus collected in October 2020 has about 20 accumulated mutations compared to the first strain sequenced in January 2020. Most mutations are either bad for the virus or have no effect. However, recently a new variant with multiple spike protein mutations is said to be 70% more contagious and now accounts for more than 60% of new infections reported in London ( It is possible that spike protein mutations could affect vaccine efficacy, but it is too early to tell whether this new, more contagious, variant is less affected by the current vaccines.

COVID-19-vaccinated individuals will need to be monitored to identify possible vaccination failure and breakthrough infections due to the new variants.


Do vaccines block transmission of SARS-CoV-2?

The phase 3 trials of the currently FDA-approved COVID-19 vaccines were designed mainly to determine each vaccine’s ability to prevent symptomatic infection and mitigate infection severity. The trials, however, did not determine whether vaccines prevent asymptomatic infection, which we know to be contagious. Thus, doctors do not know whether people who got one of the currently approved vaccines could still get an asymptomatic infection and still spread the virus.

However, one of the two FDA-approved mRNA vaccines caused a 63% reduction in asymptomatic infection between the first and second dose of vaccine. Therefore, these two mRNA vaccines with very high efficacy against symptomatic infection very likely reduce transmission to some extent. In addition, we do know that another vaccine (from AstraZeneca and the University of Oxford, not currently approved in the United States) also reduced the number of asymptomatic infected cases compared to a placebo group.


How do vaccines end an epidemic?

Not every single person needs to become immune to end an epidemic. When a large enough portion of a community becomes immune to a disease, as a result of natural infection or vaccination, person-to-person spread of disease is limited enough to halt the epidemic (called herd immunity). How many immune people in the population are required to achieve herd immunity? That depends on several factors, particularly vaccine efficacy to prevent transmission and how contagious a disease is. Doctors have estimated that about 70 to 80% of people in a population need to be immune to SARS-CoV-2 to stop the epidemic. Larger portions of the population will need to be immune to stop the epidemic if strains of the virus emerge that are more transmissible or the vaccines are less able to prevent transmission.

Until that is achieved, people will need to use other methods to reduce SARS-CoV-2 transmission. These methods include physical distancing, masking in public, staying home for non-essential workers. These restrictions must be applied to the general population, not just high-risk groups (such as the very old), because even though people outside the high-risk groups are less likely to develop severe disease, they are just as much at risk of infection and thus may spread infection to high-risk people. Also, low-risk is not no-risk—a few such people do develop severe disease and/or long-term disability.