Commentary: Update on COVID-19 Vaccines
As of mid-December 2020, The New York Times Coronavirus Vaccine Tracker listed 59 vaccines in clinical human trials, 16 of which have reached the final stages (phase 3) of testing, and at least 86 preclinical vaccines that are under active investigation in animals (1). SARS-CoV-2 vaccines are based on several different technological platforms, which determine vaccine attributes, such as the number of doses, stability at room temperature, speed of development, scalability, need for adjuvants, and cost (2).
What are the COVID-19 vaccine types?
The SARS-CoV-2 vaccines can be classified into two broad categories:
Gene-based vaccines include RNA, DNA, virus vector, and live, attenuated SARS-CoV-2 virus vaccines.
Protein-based vaccines include inactivated SARS-CoV-2 virus and viral protein or protein fragment (subunit) vaccines.
The spike protein, which studs the surface of the SARS-CoV-2 virus, contains S1 and S2 subunits. The receptor-binding domain (RBD) of the S1 subunit binds to the host cell surface receptor, acetylcholine esterase 2 (ACE2). Elements of the S2 subunit are responsible for fusion of the virus and host cell membranes. Both S1 and S2 are required for viral entry and release of its genome into the host cell. Antibodies that bind to the spike protein and block viral entry into host cells are thought to be most important for protection from disease. Because of its indispensable functions, S protein in its three-dimensional configuration is a key target for all COVID-19 vaccines in clinical development.
mRNA vaccines: SARS-CoV-2 is an RNA virus, having RNA (ribonucleic acid) as its genetic material. Several COVID-19 vaccines use the gene (in the form of messenger RNA or mRNA) that encodes the spike protein and are encapsulated in a lipid nanoparticle to deliver the viral gene into the vaccine recipient’s cells. The recipient’s cells then use this gene to synthesize the spike protein that 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 US, are currently being used to vaccinate people in multiple countries.
DNA vaccines: One SARS-CoV-2 vaccine uses DNA plasmids (small circles of double-stranded DNA) that encode the spike protein, which are introduced directly into the vaccine recipient’s cells using an intradermal injection device. 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 in its three-dimensional configuration 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. Other viral vectors used in SARS-CoV-2 vaccines include a chimpanzee adenovirus and attenuated influenza, measles, vaccinia, and vesicular stomatitis viruses.
Some of the two-dose-viral vector vaccines have used a different human adenovirus serotype or a different type of virus entirely for the first and second dose, hoping to avoid vector-specific sensitization after exposure to the first dose (ie, an immune response that attacks the viral vector, thus impeding its ability to infect recipient cells). Also, some individuals may have pre-existing immunity to the human adenovirus serotype used as the vector, which may blunt vaccine effectiveness (3).
Live, attenuated SARS-CoV-2 vaccines: Another type of vaccine consists of live, attenuated 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. Ideally, a live, attenuated virus should be rendered incapable of reversion to virulence, as has been done with the novel oral type 2 polio vaccine (nOPV) using a process called codon deoptimization (4).
Inactivated SARS-CoV-2 vaccines: These vaccines use SARS-CoV-2 virus that has been inactivated with heat, radiation, or chemicals, which terminate the pathogen’s ability to replicate.
Protein-based vaccines: These vaccines contain SARS-CoV-2 proteins or protein fragments (subunits) that stimulate a protective immune response. The viral protein can be produced by recombinant technology, in which genes that encode the viral protein. In the case of SARS-CoV-2, the spike protein or parts of it (eg, the receptor binding domain) are inserted into yeast, bacterial, or other types of cell, which then make the spike protein in the laboratory, often in large amounts; the spike protein is harvested, and the purified protein put into a vaccine. 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 (parenteral). Routes of vaccine administration other than parenteral are also undergoing evaluation in animal models and early clinical trials. For example, an intranasal route and inhaled airborne droplets—similar to how inhaled asthma drugs are formulated—could stimulate local mucosal immunity in the respiratory tract, which is critical for blocking both infection and transmission.
Is one dose of COVID-19 vaccine enough?
Many traditional childhood vaccines require a prime dose followed by a second dose, known as a booster, several weeks or with some vaccines, even years later. The booster dose strengthens immunological memory.
The two current FDA-approved vaccines are given in two doses 3 or 4 weeks apart. A single injection of either of these two-dose vaccines may provide strong protection against COVID-19. Note that several other vaccines still in the testing phase are designed to be given as a single dose, but efficacy data are pending.
One of the current vaccines (Pfizer) provides immunity in roughly half of people during the 3-week interval between the first and second dose (39 cases occurred in the vaccine group and 82 cases in the placebo group—5). But looking at data in the brief period between 12 days after the first injection (the onset of the protective immune effect) and before the second dose, an infectious disease specialist at Boston University theorized that efficacy of a single dose may be as high as 80 or 90% (6). This analysis is compatible with results of the trial of the other FDA-approved vaccine (Moderna), which looked at vaccine efficacy in a group who had received 1 dose of the vaccine or placebo at the time of the interim analysis, with a mean follow-up of 28 days. The cumulative incidence curve for cases diverged 14 days after the first dose, when the immunizing effect of the vaccine began, with more cases accumulating in the placebo group than in the vaccine group. The efficacy 14 to 28 days after a single dose was also roughly 90% (2 cases in the 983 vaccine recipients and 28 cases in the 1059 placebo recipients—7).
Because most patients in the trials of these two vaccines subsequently received a second injection, and because the follow up of those receiving only 1 injection was brief, it is unknown how long protection lasts after a single dose.
If, because of short supply, only one dose were to be given, it is unknown when it would be optimal to offer a second dose once vaccine supplies are adequate. Also, the logistics of scheduling millions of people to show up for a second dose at an unspecified point in the future is problematic. Another unknown is what the immune response and safety would be if two different COVID-19 vaccines were used for the first and second dose, a concept called “heterologous prime-boost” (8).
Will spike protein mutations weaken vaccine efficacy?
Mutations continually emerge each time the virus adapts to new hosts, despite the presence of a coronavirus RNA proofreading activity that yields high replication fidelity (9). On average, a genome from a SARS-CoV-2 virus collected in October 2020 has about 20 accumulated mutations compared to the first strain sequenced in January 2020 (Wuhan-Hu-1—reference 10). Mutations are expected and are most often simply neutral markers, useful for contact tracing.
However, mutations in genes that encode critical sites governing the interaction of the spike protein and ACE2 may alter vaccine efficacy. A spike protein mutant, called D614G, or G614, emerged in Europe and then spread quickly around the world. Fortunately, the D614G variant, which has been found to be more susceptible to neutralization by antibodies generated by earlier strains of the virus, will not likely alter vaccine efficacy (11). A SARS-CoV-2 variant with four genetic changes in the spike protein that was found in infected Danish farmed mink and mink farm workers was less susceptible to neutralizing antibodies from COVID-19 patients infected earlier in the pandemic, suggesting that antibodies generated by vaccines built on the original Wuhan spike protein may be less effective in individuals infected with this variant.
Another new variant with multiple spike protein mutations (known as VUI 202012/01 and lineage B.1.1.7) is said to be 70% more contagious and now accounts for more than 60% of new infections reported in London (12 and 13). In view of this latest UK mutant, the European CDC has recommended that genetic sequencing be done on virus isolates from suspected cases of COVID-19 reinfection and from patients in whom treatment with convalescent plasma or monoclonal antibodies has failed. With the implementation of vaccination, COVID-19-vaccinated individuals will need to be monitored to identify possible vaccination failure and breakthrough infections. Virus isolates from these patients should be sequenced and characterized genetically and antigenically to determine effects on vaccine efficacy (14).
More recently, yet another new spike protein variant, named B1.351 and 501Y.V2, has appeared in the UK; its rapid spread, first detected in South Africa at the beginning of October, could be an indication of increased transmissibility.
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. We know that up to 40% of COVID-19 infections are asymptomatic, but may, nevertheless, be contagious. The trials, however, did not determine whether vaccines block asymptomatic infection, which is well known to be transmissible. To test each vaccine’s ability to block transmission, vaccinated and placebo participants would need to be followed not only for development of a symptomatic illness, but also would need to have regular and frequent SARS-CoV-2 viral load testing of respiratory specimens. The higher the viral load in respiratory excretions, the more likely a person can transmit the virus to others. If the vaccinated group shed very little or no virus compared to the placebo group, it would be strong evidence that a vaccine reduces the chances that vaccine recipients would be contagious. At this point, it is not entirely clear whether the FDA-approved COVID-19 vaccines will therefore decrease transmission.
The second of the two FDA-approved mRNA vaccines did look at vaccine efficacy against asymptomatic infection, although the data were not available at the time of the EUA submission. To test for the possibility of prevention of asymptomatic infection, the number of PCR-positive nasopharyngeal swabs collected just before the second dose in vaccine recipients was compared with those from placebo-recipients; 14 swabs were PCR-positive in the vaccine group and 38 in the placebo group, a 63% reduction in PCR-positive swabs, suggesting that some asymptomatic infections are prevented after the first dose (Table 1, reference 15). Therefore, these two mRNA vaccines with very high efficacy against symptomatic infection very likely reduce transmission to some extent. For now, we have to await more data.
However, data are available from a trial of a currently unapproved vaccine (AstraZeneca and the University of Oxford) in which serial viral testing was done on vaccine recipients. This trial has reported that it found fewer asymptomatic infected cases in vaccinated people than in the placebo group; in their low-dose prime plus standard-dose boost trial, 7 asymptomatic cases occurred in the vaccinated group versus 17 in the placebo group for a vaccine efficacy of almost 60% in preventing asymptomatic infection (16). To test for asymptomatic infections, participants in this vaccine trial were asked to provide weekly self-administered nose and throat swabs for PCR testing from 1 week after first vaccination using kits provided by the study. Since transmissibility of COVID-19 depends not only the presence of virus in respiratory excretions, but also on the viral load, optimally viral load should have also been monitored. Viral load can be estimated by determining the threshold cycle (Ct), which is a measure of the concentration of the target gene present in the PCR reaction; the higher the Ct, the lower the concentration. However, Ct data were not provided in the published trial data (17).
Using extensive data provided by King County in Washington State, computer simulations projected an estimated 60% reduction in cases and deaths if the two FDA-approved mRNA vaccines offer complete protection against infections, both symptomatic and asymptomatic. If these vaccines primarily reduce the frequency of symptomatic illness and prevent severe infections, but do not curb the presence of SARS-CoV-2 in respiratory excretions and thus viral transmission—the computer model projects the King County region would experience about 200,000 new infections and over 500 deaths in 2021 (18 and 19). Vaccines that prevent primarily symptomatic infection are less likely to contribute to herd immunity because they may not be blocking ongoing chains of transmission (see below). Nevertheless, even if the SARS-CoV-2 vaccines do not completely block transmission, they make the disease milder and less deadly.
How do vaccines affect herd immunity?
Not everyone needs to become immune as a result of natural infection or vaccination to end an epidemic. When a large enough portion of a community becomes immune to a disease, 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. An excellent review of this topic by Marc Lipsitch (20) can be found at https://ccdd.hsph.harvard.edu/2020/12/17/covid-19-vaccines-and-herd-immunity/.
At the beginning of an outbreak, R0, called the reproduction number, is the average number of susceptible people that each contagious person infects in a totally susceptible population. R0 is thus a measure of how contagious an infectious disease is. For measles, R0 is 12 to 18, meaning that each person with measles, on average, infects 12 to 18 people. Estimates of R0 from Wuhan, China early in the epidemic were 2 to 3. After a while, transmission fell with the institution of control measures (masks, physical distancing, stay-at-home, etc.) and with more individuals becoming immune as a result of natural infection. The current reproduction number (Rt) is then less than R0. Once the Rt fell below 1 in Wuhan, the outbreak ended. Vaccines that reduce transmission, with other control measures, can contribute to decreasing transmission.
The proportion (f) of the population that must be vaccinated to end an outbreak equals (1-[1/R0])/E, where E is the vaccine efficacy to prevent transmission. If E = 95% (0.95) and R0 = 3, then (1-1/3)/E = 70% of the population that will need to be vaccinated. If the vaccine actually prevents a smaller proportion of transmissible infections, or if the virus becomes more transmissible, as the London variant is said to be, the proportion of the population that needs to be vaccinated is greater. If the vaccine efficacy to prevent transmission is less than (1− 1/R0), it is impossible to eliminate an infection solely by vaccinating even the whole population (21).
Such circumstances require use of other methods to reduce SARS-CoV-2 transmission. These methods include physical distancing, masking in public, staying home for non-essential workers. If vaccines are not optimal, it will be likely that these restrictions will need to continue for months to control transmission and ease the burden on healthcare systems. These restrictions must be applied to the general population, not just high-risk groups (eg, 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.
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10. European Centre for Disease Prevention and Control: Detection of new SARS-CoV-2 variants related to mink – 12 November 2020. ECDC: Stockholm; 2020. https://www.ecdc.europa.eu/sites/default/files/documents/RRA-SARS-CoV-2-in-mink-12-nov-2020.pdf
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12. GISAID: UK reports new variant termed VUI 202012/01. Accessed January 8, 2021. https://www.gisaid.org/references/gisaid-in-the-news/uk-reports-new-variant-termed-vui-20201201/
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