Research studies involving thousands of people have allowed scientists to test which drugs are effective at treating COVID-19. Several drug therapies are now available to treat people who are in hospital with COVID-19, or to prevent infections in vulnerable people becoming more serious. This briefing explains which drugs are available, the groups of people in which they are used and how they work. It also outlines the importance of monitoring the emergence of new variants and drug resistance.
- The SARS-CoV-2 virus spreads from one person to another largely as a result of airborne transmission. This is where a person breathes in either large or small virus-containing respiratory droplets produced by an infected individual. Evidence from epidemiological studies suggest that people with a SARS-CoV-2 infection are most infectious for the few days before and after they develop symptoms.
- Vaccines can reduce transmission in two main ways: by reducing the number of people in the population susceptible to the virus (protection) and by reducing the amount of virus that people produce when infected (viral load).
- There is good evidence from clinical trials that the vaccines currently authorised for use in the UK are highly effective at protecting people against symptomatic COVID-19 disease.
- Current estimates for the minimum proportion of the population that would need to be protected to achieve herd immunity vary, from 5–50% if the R number is between 1 and 2, to 78–85% if the R number is more than 4.
- While many counties are basing their policy response to COVID-19 on using vaccines to achieve herd immunity, the duration of protection is currently unknown. This is because clinical trials have not been running long enough to allow data collection on the medium- to longer-term effectiveness of vaccines. It is also uncertain to what extent the currently authorised vaccines will protect against new variants of SARS-CoV-2.
- Evidence is starting to emerge from clinical trials that vaccination reduces the viral load in people who were subsequently infected with SARS-CoV-2 compared with unvaccinated people. There is also preliminary evidence from clinical trials that the number of asymptomatic infections was lower in participants who had been vaccinated compared with those who had not been vaccinated.
- Further evidence on the impact of vaccines on transmission could inform decisions on how to ease lockdown restrictions as part of the UK Government’s roadmap and debate about whether to introduce an immunity certification or vaccine passport scheme.
- Experts recommend that policy decision-making on vaccine passports should consider the scientific, ethical and legal basis, as well as practical implementation, and that it should be informed by public engagement.
Modes of transmission
The SARS-CoV-2 virus can be transmitted from one person to another by three main routes:
- Breathing in droplets from, for example, coughs and sneezes. Such particles are typically 60 micrometers (µm, 1µm is 1 millionth of a metre) or more.
- Breathing in smaller airborne particles (typically 5 µm or less).
- Transmission via shared surfaces (fomites) such as mobile phones, tables and door handles.
Of these the first two are thought to be the primary routes of transmission. For example, public health advice to maintain a 2 m distance is based on evidence that this is the maximum distance that larger infectious droplets can travel before falling to the floor. This distance is longer for smaller particles, with research suggesting that particles of around 5 µm or less can travel tens of metres before reaching the ground. This route of transmission has been identified by retrospective studies as the most likely factor behind local outbreaks of coronaviruses including the 2003 SARS-CoV-1 virus and the current SARS-CoV-2 virus. In contrast, studies in a hospital setting that swabbed a variety of different surfaces have shown that inanimate surfaces, such as plastic, glass, fibers and metals, are unlikely to be a major route of transmission for SARS-CoV-2 in real-life situations.
Epidemiological and modelling studies of transmission
Research suggests that people infected with SARS-CoV-2 are most infectious in the few days before and after the onset of symptoms, with exact figures varying from one study to another. For example, a contact tracing study in Taiwan looked at secondary cases arising from the contacts of 100 index cases. It found that all secondary cases had contact with a primary case between 5 days before and 5 days after the index case developed symptoms. Another study in China applied statistical modelling to contact tracing data and found an average incubation (between infection and symptom onset) period of 4 days with a maximum infectious period of 13 days. A modelling study using epidemiological data suggested that up to 44% of transmission may occur before the onset of symptoms, with infectivity declining rapidly beyond this point and ceasing within 7 days.
How vaccines can affect transmission
Vaccines are intended to protect individuals from disease by either preventing or reducing infections or by reducing the severity of disease from infections that do occur. This protection from disease should reduce transmission rates within a population in two main ways:
- Reducing the number of people within the population who are susceptible to infection. This occurs through vaccine-induced protection in people who do not have a current SARS-CoV-2 infection (protection)
- Reducing the infectiousness of people who become infected with SARS-CoV-2. Vaccinated people become less likely to pass an infection on to others. This could happen if, for example, the vaccines reduced the amount of virus produced by an infected individual (the viral load).
There is some emerging evidence that the vaccines currently in use in the UK to protect against COVID-19 are having a wider effect on transmission.
Vaccine-induced protection and herd immunity
Vaccine-induced protection in people who do not have a current SARS-CoV-2 infection effectively reduces the proportion of the population that are susceptible to the virus. Once a sufficiently large proportion of the population has acquired immunity then the whole population is effectively protected as there are too few susceptible people for the virus to spread, a state commonly known as ‘herd immunity’.
Herd immunity can also arise from infection-induced protection. However, it is likely to have substantially higher death and disease rates and does not eradicate disease. For example, the 1918 influenza A(H1N1) pandemic was curbed by sufficient levels of infection-induced herd immunity, after more than 2 years, 500 million infections and 50 million deaths worldwide. Because variants of that influenza virus are still present, resurgence of the H1N1 subtype remains a persistent concern.
Vaccines and protection
Clinical trials are primarily designed to assess the extent to which vaccines can prevent COVID-19. There is good evidence that each of the three vaccines (Pfizer/BioNTech, AstraZeneca and Moderna) authorised for use in the UK offers a high level of protection against severe disease for individuals who have received a single dose and exposed to the virus after production of an immune response (approximately 2 weeks). For example, a study in Scotland used data from GP records of vaccination, hospital admissions, death registrations and laboratory test results to compare the outcomes of those who had received a first dose of the Pfizer/BioNTech or AstraZeneca vaccines with those who had not. It found that 4 weeks after receiving the vaccine, the risk of hospitalisation from COVID-19 was reduced by up to 85% (Pfizer/BioNTech) and 94% (AstraZeneca).
In addition to protecting against severe COVID-19 disease, there are some indications from the clinical trials that vaccination might reduce the number of infections. For example, participants in one sub-section of the AstraZeneca trial were swabbed every week and PCR tested for SARS-CoV-2 after receiving the first dose of the vaccine. There was an estimated 49% reduction in asymptomatic infections in the vaccinated group compared with the placebo group. If the protective effect of the vaccine was based solely on reducing the severity of disease (from severe to moderate or from moderate to mild) then no reduction in the asymptomatic infection rate would be expected in the vaccinated group compared with the placebo group. The researchers suggest that the observed reduction shows the vaccine “may have a substantial impact on transmission by reducing the number of infected individuals in the population”.
Similar results were reported from the Moderna trial, where researchers saw a two-third reduction in asymptomatic infections among the group that received the first dose of the vaccine compared with those receiving placebo. A recent study in the US of 3,950 healthcare and other essential frontline workers found an 80% reduction in positive PCR test results 14 days after vaccination with a single dose of either the Pfizer/BioNTech or Moderna vaccine compared with unvaccinated colleagues. This rose to 90% 14 days after receiving a second dose. These results are consistent with the vaccines helping to prevent infection, but more studies are needed to confirm this.
Further evidence on the potential impact of vaccination on transmission comes from linkage studies of healthcare workers and their household members. One recent such study looked at COVID-19 cases among the household members of healthcare workers. It found a 30% reduction in COVID-19 cases among household members of healthcare workers who had received at least one dose of vaccine (Pfizer/BioNTech or AstraZeneca) more than 14 days previously compared with household members of unvaccinated healthcare workers. The researchers noted that this reduction was “consistent with an effect of vaccination on transmission”.
Herd immunity threshold
The proportion of a population that need to be vaccinated in order to achieve herd immunity depends on the effective reproduction number (R) of the of the virus in that population. R is the average number of people infected by each individual who has the virus as measured in real-life situations, and can vary over time (depending on the measures put in place to contain the infection) and from one infection to another. For example, in the case of a highly infectious disease, such as measles, where each infected person typically passes the disease on to between 12 to 18 other people, herd immunity requires the vaccination of a very large proportion (92–94%) of the population.
In March 2020, researchers estimated R for outbreaks of SARS-CoV-2 in 32 countries around the world. They found that it varied from over 6 (in Bahrain) to slightly more than 1.0 (in Kuwait) and used these estimates to calculate the minimum proportion of the population that would need to be protected to achieve herd immunity. In those countries where R was greater than 4, they estimated that between 78–85% of the population would need to be protected to achieve herd immunity. The equivalent figures for R between 2 and 4 were 56–75% and for R between 1 and 2, 5.7–50%.
Duration of protection
While many counties are basing their policy response to COVID-19 on using vaccines to achieve herd immunity, questions remain over the duration of that protection. This is because the clinical trials that assess the efficacy of the vaccines have not been running long enough to allow data collection on medium- to longer-term efficacy. Experience of infection-induced protection against SARS-CoV-2 suggests that levels of antibody wane within months of recovery from infection. Vaccine-induced protection may have a longer duration because antibodies are just part of the complex human immune response to vaccination. Experience with other coronaviruses suggests that protection may persist for between 12 to 18 months. Another uncertainty is the extent to which the currently authorised vaccines will protect against new variants of SARS-CoV-2 and there are documented examples of individuals becoming re-infected with a different variant of the virus.
Vaccine-induced viral load reduction
Vaccines may also reduce transmission of the virus by reducing the quantity of virus carried by an infected individual (the viral load). This could potentially reduce both the severity of the disease experienced by that individual and the chance of them transmitting the infection to others.
Measuring viral load
There are two main ways of detecting the presence of SARS-CoV-2 virus. The first of these is viral culture studies, which can be used to determine whether an individual is infected with viable SARS-CoV-2 virus. The second approach is via PCR diagnostic tests. These tests use probes that bind to viral RNA and then undergo successive rounds (cycles) of amplification until detectable levels are achieved. The number of cycles needed to detect RNA (the cycle threshold) can be used as an indication of the viral load; the larger the cycle threshold, the lower the viral load. Unlike viral culture studies, positive PCR tests results are not necessarily indicative of the presence of viable virus.
These methods have been used to study variations in viral load over the course of SARS-CoV-2 infections. Such studies suggest that:
- Viral load varies from one sample site to another. The highest viral loads are found in the upper respiratory tract around the time of onset of symptoms. Viral loads in sputum samples from the lower respiratory tract peak later, typically around 2 weeks after symptom onset, although there is more variation in these samples.
- There is a clear correlation between viral load and severity of symptoms, with PCR tests finding viral loads 10–60 times higher in patients with severe symptoms compared with mild cases.
- Viral RNA loads start to decline within a few days of symptom onset but remain detectable (by PCR tests) for up to 3 weeks in samples from the upper respiratory tract.
- While viral RNA can be detected for up to 3 weeks after symptom onset using PCR, viral culture studies can only isolate viable virus from SARS-CoV-2 cases for up to 9 days after the onset of symptoms.
- There are no significant differences in either viral loads or duration of detectable virus between adults and children.
Viral load and transmission
Viral load is a proxy measure of infectivity, so any decrease in it may not be directly translated into reduced transmission. A recent study in Israel, that has yet to be peer-reviewed, provides more direct evidence of the impact of vaccine on viral load. It identified 2,897 cases of COVID-19 among more than 650,000 people who had received their first dose of the Pfizer/BioNTech vaccine. The researchers matched these cases by sex and age to the same number of unvaccinated COVID-19 cases and compared the viral load of the two groups. 1,755 cases occurred between 1–11 days after vaccination, with the remaining 1,142 cases being between days 12–28. No significant differences in viral loads were found between the vaccinated cases and their unvaccinated matches for the cases that occurred between 1–11 days. However, for those infections that occurred 12–28 days after vaccination (after the point where immune responses to the vaccine will have been induced), viral loads were on average four times lower in the vaccinated group compared with their unvaccinated counterparts. The authors suggest that these findings “hint to lower infectiousness, further contributing to vaccine impact on virus spread”.
Policy implications of reduced transmission
There is good evidence that vaccines are one of the factors helping to reduce transmission rates of SARS-CoV-2 in the UK. More evidence on the role of vaccines in reducing transmission will emerge in the coming weeks and months as more data are collected from ongoing clinical trials and research. Further evidence on the impact of vaccines on transmission could inform policy decisions in two key areas:
- The rate of easing of current lockdown restrictions.
- The ongoing debate about immunity certificates and vaccine passports.
Easing of current restrictions
On 22 February 2021 the Prime Minister laid out a four-step roadmap to ease restrictions across England and provide a route back to a more normal way of life. The roadmap notes that there is a minimum of 5 weeks between each step: 4 weeks to allow for collection and analysis of data on the impact of the restrictions eased and 1 week to provide notice of any further changes. The impact assessment will be based on four tests:
- whether vaccine deployment has continued successfully;
- vaccines are effective in reducing hospitalisations and deaths;
- infection rates do not risk a surge that would put unsustainable pressure on the NHS;
- the assessment of risk is not fundamentally changed by new variants of concern.
Any new evidence on the impact of vaccines in reducing transmission would be highly relevant to the second of these tests and could inform policy decisions on easing restrictions.
People who have recovered from COVID-19 may have acquired a degree of infection-induced protection and be less likely to transmit the virus to other people. Since the early days of the pandemic there has a been an ongoing debate about the pros and cons of allowing recovered COVID-19 patients a greater degree of freedom from the general restrictions in place to protect public health based on this presumed lower risk of transmission. In the early stages the focus of this debate was on whether these individuals could be distinguished from others who were more susceptible, through testing for the presence of antibodies from prior infection with SARS-CoV-2. Antibody testing was seen by some at that time as a way to assess an individual’s risk of being infected and transmitting the virus to others and as the potential basis of a system of ‘immunity certification’. In April 2020, the World Health Organization (WHO) reviewed the evidence on immunity passports and put out a statement saying that, at that time, there was “not enough evidence about the effectiveness of antibody-mediated immunity to guarantee the accuracy of an immunity passport or risk-free certificate” and that “the use of such certificates may therefore increase the risks of continued transmission”.
In June 2020, the Nuffield Council on Bioethics (NCoB) published a briefing considering the ethical questions raised by antibody testing and immune certification. NCoB argued that it raised many ethical questions concerning respect for individual rights and interests, public health responsibilities, and social justice. They concluded that at that time there was too much scientific uncertainty and too many unresolved ethical concerns to support the use of immunity certification as a way of easing restrictions on certain members of the public. They also noted that regulatory measures may be needed to secure the benefits of testing while defending against morally unacceptable and socially undesirable consequences. By contrast, a group of academics at the University of Oxford published an article on the scientific and ethical feasibility of immunity passports in October 2020, responding to ethical arguments against immunity passports. They argued that individual and social benefits were likely to accrue from allowing people to engage in free movement, where feasible, and that challenges relating to the implementation of immunity passports ought to be met with targeted solutions to maximise their benefit.
Since the deployment of vaccines from December 2020, the debate has shifted to focus on vaccine passports. A report published by the SET-C (Science in Emergencies Tasking: COVID-19) group at the Royal Society in February 2021 outlines 12 criteria that it considers should be satisfied to deliver an effective vaccine passport. The Ada Lovelace Institute also published findings from a rapid expert deliberation to consider the risks and benefits of the potential roll-out of digital vaccine passports in February 2021. While the focus of the expert reviews differs, they both suggest that any form of vaccine passport is likely to need at least three components: proof of vaccination, immunogenicity test results to show that an immune response has been induced, and a recent PCR test result that is negative for SARS-CoV-2.
Based on the evidence available before February 2021, both studies concluded that understanding around the technical basis of such approaches or the ethical implications of their use were not sufficient to warrant introducing a scheme at that time. However, both noted that this is likely to change as more data emerge from clinical trials and made recommendations as to what policy decision-making on vaccine passports should take into account now, including:
- The scientific basis. Includes the standards of evidence required for passport holders to be considered protected from illness and unable to transmit SARS-CoV-2 to others. This evidence should take into account differences in vaccine effectiveness, changes in efficacy against new SARS CoV-2 variants, the impact of vaccines on transmission of the virus and the duration of vaccine-induced immunity.
- The ethical and legal basis. With regard to human rights, data protection, equality and discrimination, health and safety, and employment law. There is consensus that this should include engaging the public before the introduction of any such system, to understand impacts, build trust and legitimacy, and understand what trade-offs the public is willing to make.
- Practical implementation. For example, international standards, verification and inter-operability between platforms and data security. The Ada Lovelace Institute recommended consulting experts likely to be involved in the practical implementation of any use.
Many of the key issues around vaccine passports surround fair use. This includes what it could be used for, for example, whether it is a passport to allow international travel or domestically to allow holders greater freedoms. Two of the lead authors of the SET-C report argue that the intended use will have significant implications across a wide range of legal and ethical issues. It could inadvertently discriminate or exacerbate existing inequalities. For example, if people for whom vaccination is unacceptable, untested, inaccessible or impossible are denied access to essential goods and services. They note this could happen where there is vaccine hesitancy or refusal among certain ethnic minorities; where there are no data on vaccine efficacy for people at risk, such as children and pregnant women; where migrants are undocumented and unreachable; where passports are exclusively digital, barring people without smartphones; and where people are not yet eligible for vaccination. They argue that these examples signal the need for alternatives and exemptions.
In response to an e-petition titled “Do not rollout Covid-19 vaccine passports” that received more than 300,000 signatures, on 3 March 2021 the UK Government said it was “reviewing whether COVID-status certificates could play a role in reopening parts of our economy, reducing restrictions on social contact and improving safety.” The topic was subsequently debated in the House of Commons on 15 March. The Paymaster General responded that the details of what the review will consider had been published on that day.
This consultation document defined COVID-status certification as “the use of testing or vaccination data to confirm in different settings that individuals have a lower risk of getting sick with or transmitting COVID-19 to others. Such certification would be available both to vaccinated people and to unvaccinated people who have been tested.” The consultation stated that the UK Government is considering the ethical, equalities, privacy, legal and operational aspects of a potential certification scheme and what limits, if any, should be placed on organisations using certification. It was open from 15 to 29 March 2021 and the review is expected to report by June 2021.
On 17 March 2021 the European Commission (EC) proposed a “Digital Green Certificate” to “facilitate safe free movement inside the EU during the COVID-19 pandemic.” The EC stated that this would be temporary and “will be a proof that a person has been vaccinated against COVID-19, received a negative test result or recovered from COVID-19.” The EC stated the aim was to have the technical work and the proposal completed in the coming months, to be ready before the summer.
The WHO has established a Smart Vaccination Certificate (SVC) Working Group to establish interoperability standards for digital documentation of vaccination status for COVID-19 vaccines, with intended applicability to other vaccines. However, the SVC only documents that a vaccination event has occurred – it is not intended to serve as an “immunity passport” – and as of March 2021, the WHO does not recommend proof of COVID-19 vaccination as a condition of departure or entry for international travel. The WHO is consulting on interim guidance for developing an SVC until mid-April 2021.
The Ada Lovelace Institute is tracking international developments in policy and practices around vaccine certification and COVID status apps.
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