How will a COVID-19 vaccine work? A brief insight into 2020's most important issue

The coronavirus disease (COVID-19) pandemic has caused global disruption and malady but also ignited collective efforts to combat the outbreak. Short term solutions such as physical distancing are the cornerstone of global efforts to prevent the spread of the causative virus, SARS-CoV-2, yet vaccine development is the primary focus for long-term prevention. While COVID-19 vaccine development has received considerable media attention, some key questions remain such as how a vaccine will work, who could get vaccinated, and what protective immunity might look like.

So, what are vaccines and how do they work?

In brief, vaccines are typically inactivated copies or parts of a germ that are used to train the body to recognise the germ before we encounter the real thing in everyday life. This is important for the following two reasons: 1) your body learns how to destroy the germ and remembers how to do it (called immune memory) and; 2) a faster, more efficient, and powerful immune response, because of immune memory, may prevent an otherwise life-threatening disease. In the same way you may train for a marathon to give yourself the best chance of crossing the finish line on race day, you can give yourself the best chance of surviving a dangerous infection by vaccination. History tells us that a trained immune system can be the difference between life and death.

So how will a COVID-19 vaccine work? Let’s think about our goal.

A COVID-19 vaccine needs to protect those most at risk of developing severe life-threatening COVID-19 disease if they get infected. While preventing infection is optimal, simply preventing progression to severe disease may be enough. This is because death is a result of severe disease, not of infection. After all, death does not occur in 100% of cases. Those who are most likely to develop severe disease include the elderly and those with underlying health conditions who may have weakened immune systems. Frontline workers who are routinely at risk of virus exposure may also benefit from a vaccine.

Protection from vaccination could be achieved in two ways.

The first way is by vaccinating the general population against the virus. Therefore, high-risk individuals or those who cannot be vaccinated due to underlying health conditions or pregnancy, are indirectly protected from acquiring the virus as the transmission rate will be very low (as everyone clears the virus infection quickly because of vaccine-induced immune memory). This form of protection is called herd immunity.

Herd immunity can also be achieved through naturally acquired infection, which has received plenty of media attention. However, considering the high threshold to achieve herd immunity (in the range of 60-80% of the population) in combination with the death rate of high-risk groups, many people are put at risk if naturally acquired herd immunity is pursued. Indeed, increasing mortality rates in some countries may be explained in part by less stringent physical distancing practices.

Herd immunity is subject to further scrutiny considering the limited scientific evidence demonstrating that people are protected from SARS-CoV-2 reinfection, evidence from a recent study in Spain. A lack of sustained immune memory in recovered individuals may undermine naturally acquired herd immunity.

Even if we find evidence demonstrating that recovered patients are protected from reinfection, how long this immunity lasts for is unknown and remains an important unanswered question. Recurring bouts of other respiratory infections, such as flu and other less dangerous coronaviruses, suggest that immunity may wane over time. Whether SARS-CoV-2 becomes a recurring infection is not yet clear but short-lived immunity to this virus could undermine herd immunity, whether through vaccination or natural spread.

The second vaccination strategy is to directly vaccinate high-risk groups. This approach will protect these individuals from acquiring COVID-19 disease even if the virus continues to spread. This strategy also relies on generating immune memory to protect from reinfection or at least progression to severe disease. Fortunately, scientists can specifically design vaccines to give the best chance of generating certain types of immune response—including long-lasting immune memory—using different vaccine technologies.

One example of vaccine technology being used for SARS-CoV-2 is a viral vector vaccine. This vaccine is a harmless common cold virus called a chimpanzee adenovirus (ChAd for short) that encodes the genetic sequence of the SARS-CoV-2 Spike protein (or any other protein of interest). The adenovirus vector acts as a delivery system by which it enters host cells and starts producing the Spike protein to incite an immune response from the host. The University of Oxford has partnered with the pharmaceutical company, AstraZeneca, to scale up the production of their COVID-19 viral vector vaccine—ChAdOx1 nCoV-19—should human trials give promising results. Pre-clinical testing has already reported this vaccine prevents disease onset and critically, does not exacerbate disease after infectious challenge in Rhesus macaques. Furthermore, a recent report of a phase I/II trial has shown that this vaccine can generate a robust immune response targeting the virus' Spike protein in healthy people. The ChAdOx1 nCoV-19 vaccine is now in large-scale Phase III testing on multiple continents to determine if the vaccine protects from SARS-CoV-2 infection and disease in humans. Other institutions and companies are pursuing viral vector vaccines including CanSino Biological Inc and the Beijing Institute of Biotechnology who are using the well-established human adenovirus (serotype 5) technology.

Another promising COVID-19 vaccine candidate, from Moderna, uses an mRNA vaccine (a short sequence of SARS-CoV-2 genetic material that encodes the viral Spike protein). In the same way a viral vector can deliver DNA to a host cell, genetic material such as mRNA can be taken up directly by immune cells leading to virus protein production (from the mRNA template) and generation of an immune response to that viral protein. These types of vaccines can be produced quickly and inexpensively and are also in human trials. Phase I data demonstrated that this mRNA vaccine can generate an immune response in healthy people. However, whether this vaccine elicits protective immunity will not be known until the conclusion of phase III human testing which is scheduled to begin in the US in late July.

Currently, there are over 200 vaccines under development and time will tell which ones will be used to curb the pandemic.

Yet with powerful vaccine technology at our disposal, how do we know what a protective immune response will look like?

The gold standard is to conduct human trials to reveal any difference in protection against infection and disease between the vaccinated group and the unvaccinated control group (or a group immunised with an irrelevant vaccine). As this data takes time to acquire, another quicker and complementary method is to compare immune responses in recovered COVID-19 patients to those in vaccinated healthy people. Recovered COVID-19 patients have displayed both virus-inactivating antibodies (called neutralising antibodies that bind to viral surface proteins such as the SARS-CoV-2 Spike protein and prevent infection of human cells) and T cells (white blood cells that destroy a virus-infected cell). Collectively, antibodies and T cells provide two tiers of immunity. Therefore, a vaccine that can induce both antibodies and T cells may be optimal. In time, vaccine clinical trials will reveal which responses are protective.

Healthcare systems must reliably identify recovered individuals in clinical trials, and more broadly in the general population to inform government and policy decision making. However, there are potential confounding factors. One important consideration is the potential for inaccurate testing results. For example, false-positive results may arise due to the cross-reactivity of antibodies and T cells specific for other harmless coronaviruses that circulate in the general population. What this detected cross-reactivity means in terms of disease, be it protective, antagonistic, or simply irrelevant, is unclear. Conversely, false-negative results may appear if testing is performed too early after initial infection (antibodies typically peak at day 28 post-infection) or if only one component of the immune response primarily mediates virus clearance (e.g. T cells or antibodies). Therefore, both antibody and T cell analysis should be a part of routine patient testing.

While our best available methods to prevent COVID-19 spread is physical distancing and quarantine, the ideal long-term strategy is vaccination. Only time will tell which vaccine candidate is up for the job and finding the answers to the many uncertainties in vaccine development. However, our collective efforts in fighting COVID-19 within and beyond the scientific community provide many reasons to be optimistic for producing an effective vaccine against SARS-CoV-2 in the near future.