Status of COVID-19 vaccine development

Biology and antigens

SARS-CoV-2 is an enveloped positive-stranded RNA virus in the family Coronaviridae. There are more than 35 known coronaviruses (6) that infect various mammals, including bats, pigs, cattle, chickens, dogs and cats (7). Seven of these viruses can currently infect humans. The virus family is further divided into four genera: alpha, beta, gamma and delta coronavirus. SARS-CoV-2 is a beta-coronavirus, as are two other feared human-pathogenic coronaviruses with epidemic potential, namely SARS-CoV-1 and MERS-CoV (Middle-East respiratory syndrome coronavirus).

In 2003, SARS-CoV-1 caused a major global outbreak that spread rapidly from the Guangdong province in China to at least 26 different countries, resulting in 8 096 infections and 774 deaths (8). MERS-CoV has to date mainly caused outbreaks limited to the Arabian Peninsula, with more than 2 000 confirmed cases and over 700 deaths (9). Additionally, four coronaviruses circulate in the population and give rise to colds and respiratory tract infections of varying severities, but rarely cause serious illness. These viruses, two of which are beta-coronaviruses (HCoV-HKU1 and HCoV-OC43) and two of which are alpha-coronaviruses (HCoV-229E and HCoV-NL63), are thought to cause 15–30 % of all respiratory tract infections (7).

The genome of SARS-CoV-2 consists of approximately 30 000 nucleotides and encodes four structural proteins referred to as spike protein (S), membrane protein (M), nucleocapsid (N) and envelope protein (E) (10) (Figure 1). The genome also encodes 23 non-structural proteins, including an RNA polymerase (10, 11). S proteins characterise all coronaviruses: they cover the surface of the virus and resemble a corona on electron microscopy, hence the family name Coronaviridae. The S protein of SARS-CoV-2 contains a domain that interacts with the human receptor angiotensin-converting enzyme 2 (ACE2), which facilitates uptake of the virus into the body’s cells (12). SARS-CoV-1 and the common cold virus HcoV-NL63 also use this uptake mechanism, but the other coronaviruses do not (2, 13). ACE2 is expressed on epithelial and endothelial cells, including lung tissue, intestines, kidneys and heart (14).

Figure 1 Schematic illustration of SARS-CoV-2 showing the four structural proteins: spike protein (S), membrane protein (M), envelope protein (E) and nucleocapsid (N). The S, M and E proteins are anchored in the lipid bilayer that makes up the viral membrane. The N protein is associated with viral RNA on the inside of the membrane. Modified from Desiree Ho, the Innovative Genomics Institute. CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0).

The S protein is the primary antigenic target in the development of vaccines against SARS-CoV-2 (Figure 2), the aim being to generate an immune response that prevents the virus from interacting with ACE2. Specifically, the vaccine molecule should mimic epitopes in the area of the S protein that is in direct contact with the human receptor, the receptor binding domain (RBD). It is now well established that an immune response to the S protein is generated as a result of infection with SARS-CoV-2, and in vitro studies with convalescent sera have shown that anti-S antibodies are able to neutralise the virus in cell culture and prevent its interaction with ACE2.

Figure 2 3D printed structural model of the spike protein (S) of SARS-CoV-2 viewed from the side. The S protein is the primary antigen in vaccines against COVID-19. It is a surface-exposed glycoprotein composed of three identical protomers and undergoes a structural change when it binds to the human receptor angiotensin-converting enzyme 2. In the figure, one protomer is given colour, with green indicating the receptor-binding domain. A model of a SARS-CoV-2 virus particle can be seen in the background. From the National Institute of Allergy and Infectious Diseases (NIAID) / CC BY (https://creativecommons.org/licenses/by/2.0).

The three other structural proteins (M, N and E) are not currently considered as important in the context of a vaccine, and the relevance of antibodies against these antigens is unclear. The N protein is not a surface protein, but is associated with viral RNA within the membrane that surrounds the virus. However, antibodies against the N protein are also formed during infection with SARS-CoV-2 (15, 16), and previous development of vaccines against SARS-CoV-1 has shown that the N protein can generate T cell responses that confer immunological memory (17). The inclusion of T cell epitopes located on the N protein may therefore be important for achieving immunity to COVID-19.

Vaccines against COVID-19

When the severity of the global threat posed by SARS-CoV-2 became apparent, multiple institutions, vaccine manufacturers and research groups engaged in the task of developing a vaccine. During the first few months of 2020 alliances and collaborations were established between major players in the vaccine industry, both in academia and in the commercial sector, and a number of vaccine candidates were launched. Several of the groups had previous experience with the development of vaccines against SARS-CoV-1 and MERS-CoV, and were able to quickly adapt these vaccines for use against SARS-CoV-2.

The WHO maintains a running list of candidate vaccines in development (18), and as of August 28^th 2020, there were 142 registered vaccine candidates in the preclinical stage and an additional 31 in clinical trials (Table 1).

Vaccine development: other considerations

The development of a new vaccine is a highly complex and expensive process that usually takes many years, but which is currently taking place at unprecedented speed with many processes operating in parallel and with enormous financial support (28). Some important variables that must be studied for each vaccine candidate are the dose of antigen, dosing regimen, mode of administration and possible use of adjuvant. Also important are in-depth analyses of possible side effects, which are often closely related to vaccine dose. Here, there are limits on the extent to which the time frame can be compressed, as increased safety in terms of ruling out side effects is achieved through longer observation time and large phase 3 trials.

There are several examples of side effects that can pose a real challenge. The most feared is so-called antibody-mediated enhancement, in which vaccinated individuals may be at increased risk of serious illness if they become infected. Such an effect has been observed previously for vaccine candidates against respiratory syncytial virus (RSV) and dengue virus (29, 30). Animal experiments indicate that this may also be a challenge for the development of vaccines against coronaviruses (31–33). It is therefore important to test many different types of vaccines, preferably also with different antigens, to ensure that we can ultimately select effective vaccines that induce a safe immune response.

The upscaling and mass production of a vaccine is in itself a huge challenge when hundreds of millions, or possibly even billions, of doses are required. Precision and quality must be ensured at all stages, including appropriate transportation, storage and handling of the vaccine prior to it reaching the individual to be vaccinated. A political tug-of-war can be expected when the first doses of vaccine are to be distributed. Several international organisations will have an important role to play here, including the WHO, the vaccine alliance GAVI, and CEPI (the Coalition for Epidemic Preparedness Innovations). The latter, which was established in Norway and has its headquarters in Oslo, is providing major financial support to several of the leading vaccine candidates and is working to achieve a fair global distribution of vaccines. US authorities have launched a separate initiative called Operation Warp Speed, which is providing major financial support to selected vaccine candidates with the primary goal of securing US interests.

With respect to the various stages of clinical trials (Table 2), it should be noted that phase 1 studies are typically conducted in young, healthy adults, whereas it is the elderly who are most at risk of severe COVID-19. The elderly often also respond less well to vaccination. To date, clinical trials have primarily been performed in young adults, and therefore little is known about the effect of the various vaccines in the elderly. Although immune responses are evaluated in phase 1 and phase 2 trials, it is only in large-scale phase 3 trials that protection against disease is investigated.

Conclusion

The development of techniques for vaccination is one of the biggest and most important achievements in the history of medicine, at times so effective that we forget just how important vaccines are. In the face of the humanitarian and economic catastrophe that is now unfolding as a result of the ongoing pandemic, a huge amount of attention has been focused on the development of an effective vaccine against COVID-19, and great hopes have been pinned on its success. At the time of writing, at least 173 vaccine candidates are under development and six have entered phase 3 trials.

The picture so far is that several of the candidates have been judged safe enough for use in humans and have been shown to generate relevant immune responses towards SARS-CoV-2. What we will not know until the results of the phase 3 trials become available, however, is whether these immune responses provide protection against COVID-19. History has taught us that many promising vaccine candidates disappoint when their protective effect is evaluated in large clinical trials. As for the duration of immunity, we can at present only speculate.

The achievements of the last six months in the vaccine field have shown that when the need is great enough and the global community focuses its efforts on a single defined goal, processes that usually take many years can be compressed into a few months. This is partly because regulatory authorities have given the matter top priority, and partly because of the enormous financial resources available and a willingness to take financial risks. However, another key reason is the so-called ‘platform technologies’ used by the vaccine industry. The trend is increasingly towards the development of universal vaccine platforms into which new antigens can quickly be integrated to counter a new epidemic threat.

If there is one thing the pandemic has taught us, it is that investing in epidemic preparedness should be a top priority if we are to maintain the way of life, standard of living and freedom of movement we all desire. The pandemic caused by SARS-CoV-2 is not the first, and will certainly not be the last, to hit mankind. The viruses will keep on coming, and the solution will often be a vaccine.