Human challenge studies in the study of infectious diseases
What can deliberately infecting healthy people tell us about infectious diseases? How is this useful for developing treatments, and how do we manage the risks?
The Omicron variant of the SARS-CoV-2 virus, which causes COVID-19, has been found across the world since it was first detected in early November 2021. This article describes the characteristics of the variant and its health impacts. It also discusses vaccine effectiveness against the variant and the medium and long-term outlook for the future course of the pandemic.
This is a fast-moving issue and should be read as correct at the time of publication.
POST’s December 2021 article on the Omicron variant describes how viral mutations occur, why they matter, and how new variants are detected and tracked. It also explains the mutations seen in Omicron. These mutations give the virus properties that have allowed it to out-compete other variants that were circulating. Omicron has rapidly replaced the Delta variant and become the dominant SARS-CoV-2 variant responsible for infections. Omicron now accounts for almost all COVID-19 infections in the UK.
When Omicron emerged, there was considerable uncertainty about its impact on the course of the pandemic. This is the case with the emergence of any new variant, especially those that out-compete others. New variants can have characteristics that could present a risk for causing more severe disease, more deaths, increased transmissibility, resistance to treatments, or for evading immunity conferred by vaccination or previous infection. This article highlights key findings that have emerged since Omicron was detected.
Real-time analysis on the variant’s spread meant that it became quickly clear the variant is more transmissible than Delta, as it rapidly became the dominant circulating strain. This is linked to the variant’s ability to evade immunity resulting from previous infection or vaccination. The interval between being infected and that person infecting others is also shorter for Omicron than for Delta.
There is evidence from a range of sources to support the initial indications that infections caused by Omicron are less severe than those caused by Delta. Understanding the role of previous infection or vaccination status in reducing risk from Omicron is complex. In the recent wave of infections, the risk of being hospitalised with an Omicron infection was between 35–65% lower when compared with a Delta infection in those who had received 2 doses. Of those admitted to hospital, patients with Omicron infections tended to require fewer interventions, have shorter stays and have better outcomes overall. This results from two main factors:
However, infections caused by Omicron can still cause serious illness, especially in those who are not fully protected by vaccination or in groups who are inherently more vulnerable to COVID-19, such as the elderly. From the latest data available published on 28 January 2022 (England) of those patients hospitalised and needing critical care in December 2021, 61% were unvaccinated.
Some people will experience a COVID-19 infection more than once during the course of the pandemic, called a reinfection. This is expected, even in people who are fully vaccinated. A reinfection can be with the same or different variant. Interpreting reinfection data is not straight forward, with complexity arising from which variants are involved in primary and subsequent infections, the relative role of and strength of immunity derived from vaccination and infections (which vary as someone encounters the same or different variants), and how reinfections are defined.
A research study (that has not yet been peer reviewed) analysed how having a previous infection can protect against Omicron. A prior infection offers good protection against a symptomatic reinfection against Alpha, Beta and Delta variants. However, protection against Omicron reinfections was much lower, at 60%.
In England reinfections have been counted in national case numbers since 31 January 2022, and are defined as someone experiencing a new infection at least 90 days after the last one. Analysis from two surveillance studies shows that before Omicron, the average proportion of all infections due to reinfection was low, with an average reinfection rate of 1.4% until mid-November 2021. Since mid-December, when the Omicron wave began, there has been a sharp increase, with 10% of cases designated as reinfections. This trend is also captured in high quality surveillance studies:
This is related to the variant’s ability to partially evade immunity together with waning levels of immunity in the population. Reinfections are usually, but not always, less severe than the first infection. Reinfections will occur with increasing frequency as people are repeatedly exposed to the virus.
Vaccine effectiveness is determined by comparing rates of disease in vaccinated and unvaccinated groups. Effectiveness is calculated for specific outcomes that give us extra information about how well a vaccine can prevent:
Soon after Omicron emerged, it become clear that vaccine effectiveness was lower than for Delta, because Omicron causes symptomatic infections even in people who have completed a primary course of immunisation (1 or 2 doses [depending on the vaccine used] for adults and children aged over 12 years, 3 doses for clinically vulnerable people). In response, the Joint Committee on Vaccination and Immunisation (JCVI) recommended an enhanced and expedited COVID-19 vaccine booster programme in December 2021. Boosters offer very high levels of protection against the risk of developing severe disease, being hospitalised and dying. This level of protection is likely to be better maintained than the protection against developing a mild infection. The duration of this high-level protection is unknown, but likely to be at least two to three months.
Vaccine protection against being hospitalised with COVID-19 is high, especially after 3 doses. Vaccines offer 90% protection after a Pfizer booster and 90–95% after a Moderna booster. Data show that this protection wanes over time, with protection from Pfizer dropping to 75% after 10–14 weeks. The high level of protection from Moderna endures for up to nine weeks. The UK Health Security Agency (UKHSA) estimates that the booster programme has prevented 130,200 hospitalisations between 13 December 2021 and 6 February 2022.
Vaccine effectiveness against death is also very high. After 3 doses, irrespective of which booster is used, vaccine effectiveness in preventing death is 95%.
People with a mild symptomatic infection may go on to develop a more serious illness. Vaccines can prevent such mild infections developing, but vaccine protection against mild infections wanes more quickly compared with protection against hospitalisation and death.
After 2 doses of the AstraZeneca vaccine, protection against symptomatic Omicron infections is 45–50%, with limited or almost no protection 20–25 weeks after dose 2. UKHSA publishes weekly data on vaccines. Two to four weeks after a booster of either Pfizer or Moderna, effectiveness increases to 60–75%, then falls to 25–40% 15 weeks after the booster dose. Vaccine effectiveness is slightly higher in younger age groups.
By preventing people becoming infected, vaccines also prevent infections spreading (transmission). Vaccinated people who become infected are less likely to pass the infection on since they tend to have a shorter infectious period and they produce fewer infectious viral particles. While vaccines reduced Delta variant transmission by up to 42%, there is no data yet about Omicron transmission.
Research is underway to determine how well boosters protect people against having asymptomatic (no symptoms) infections.
As of 28 February 2022, UK vaccine coverage data showed that one third of eligible people (those aged 12 years and over) had not had a booster vaccination (or third dose). Uptake in older age groups is very high (90% in those aged over 70) and declines across younger age group (74% of 50–54 year olds, 57% of 40–44 year olds, 42% of 30–34 year olds). The figure below shows the decline and subsequent plateau in take up of a third dose or booster since December 2021.
There are some other significant differences in take up of boosters across regions and in some groups. London has the lowest take up of boosters, at just under 60%. Take up is highest in the least deprived areas of England (84%) compared with the most deprived (53%). Booster vaccine take up is lowest in Black and Pakistani adults (less than 35%). Unvaccinated pregnant women are at higher risk of being severely ill with COVID-19. Of 235 pregnant women in intensive care between January and September, none had received 2 doses of vaccine. Vaccine take up is low in this at-risk group; for those who gave birth in October 2021, 29.4% had received 2 doses (coverage was lower in Black women at 6.8%, and 16.7% in Asian women). This prompted an announcement from UKHSA on 27 January 2022 to urge pregnant women to get vaccinated.
Common to all viruses, the SARS-CoV-2 virus has evolved since it was first identified, and the family tree of variants is growing. It contains separate large groupings of closely related variants (called lineages) including Alpha, Delta and Omicron. Each lineage has a number identifier (BA.1 for Omicron). Scientists are tracking a sister branch to Omicron, called BA.2; BA.1 and BA.2 have a common ancestor. Scientists are tracking the spread of these two variants and monitoring whether there are differences in the type and number of infections they cause, and if vaccines are effective against both.
The BA.2 variant has some of the same mutations as Omicron and some differences. The first BA.2 case in the UK was detected by genetic testing on 6 December 2021. The overall proportion of BA.2 infections in the UK is growing, with 31,904 confirmed cases in England as of 22 February 2022. Genomic sequencing analysis tells us what proportion of infections are caused by each circulating variant; latest data shows that BA.2 is now the most common variant in Northern Ireland and England.
The World Health Organization and the UKHSA have reported some early findings. Early data show that BA.2 has a growth advantage (characteristics that favour it) and is slightly more likely to cause infections in household contacts when compared with BA.1. UKHSA has done a preliminary analysis to compare vaccine effectiveness against symptomatic disease for BA.1 and BA.2 infections. The levels of protection are similar, with overlapping ranges of effectiveness at both 2–4 weeks after a booster (68–77%); this wanes over time (falling to 37–53% 10 weeks and over after a booster).
Early indications are that BA.2 infections do not cause more severe disease or increase the risk of being hospitalised, but further research is needed to confirm this.
Omicron dominated infections in the UK in winter 2021/22 but it is not certain that this variant will continue to do so. While the emergence of new variants is certain, the timing and characteristics of variants and their impacts are highly unpredictable. Variants can differ in transmissibility, the severity of disease that they cause and their ability to evade immunity (whether induced by infection or vaccination) or to resist antiviral drugs. This has consequences for future waves of infection and the number of people affected by serious disease, hospitalisation and death. This was clearly demonstrated when Omicron emerged, causing a very large wave of infection in the UK despite high levels of population immunity.
Other factors that will influence patterns of infection in the population include the changes to infection susceptibility (as immunity wanes), changing social behaviour (notably social contact patterns) and emerging seasonal patterns that advantage the virus, which are typical of respiratory viruses such as influenza. These factors are more predictable than the emergence and characteristics of new variants. The Scientific Advisory Group for Emergencies (SAGE) has stated that future waves of infection should be expected. SPI-M, the expert scientific advisory group that provides advice for the UK Government on modelling of COVID-19, considers that it could take up to a decade for a predictable seasonal pattern of COVID-19 to emerge, preceded by an unpredictable dynamic and unstable period. SAGE also states that a constant in any scenario is the probability of continued disproportionate impacts on some groups, especially those who are unvaccinated.
Scientists agree that continued high quality global and national surveillance of emerging variants and targeted testing are critical. Early signals from this monitoring buy time for preparing for new waves of infection that could put pressure on healthcare systems, to plan appropriate countermeasures and to fully understand the potential health impacts. Genetic analysis that allows identification of new variants is also seen as critical. The UKHSA and the COVID-19 Genomics UK Consortium has led on surveillance work and identifying new variants.
Public health agencies across the UK have permanent routine infection surveillance for many infectious diseases. The future of the UK’s current COVID-19 surveillance programmes was announced in the Government’s Living with COVID-19 guidance. National test and trace data are collected from PCR and lateral flows tests and published daily on the Government’s COVID data dashboard. These data are already becoming less reliable as an indicator of infection prevalence since it is influenced by policy changes on testing and people’s behaviour around testing. From 1 April 2022, free universal testing provision will end, and will be limited thereafter to testing symptomatic people in high risk groups (these have not yet been defined) and social care staff.
High quality scientific programmes have been tracking infections, immunity and impacts of vaccination in households (COVID-19 Infection Survey), care homes (the VIVALDI study), and healthcare staff in hospitals (the SIREN study). The design of the COVID-19 Infection Survey means that it can deliver high quality results that are not affected by national policy changes on testing and changing behaviours. Testing policy changes may have impacts on SIREN and VIVALDI. The VIVALDI study has been using data from the national testing programme in its analysis. In a recent meeting, SAGE noted that the Office for National Statistics COVID-19 Infection Survey is a critical tool from the perspective of pandemic management and as a research tool. The ONS survey captures more accurate prevalence data than the data dashboard, with some scientists commenting that the dashboard data may count only 1 in 2.5 of cases. Detecting and tracking variants is also highlighted by scientists as essential. The UK Government has announced that these programmes will continue in some form. The COVID-19 infection survey will be scaled down, but there are no details on this. The duration of continued funding support for SIREN and VIVALDI is unclear.
Photo by Jan Kopřiva on Unsplash
What can deliberately infecting healthy people tell us about infectious diseases? How is this useful for developing treatments, and how do we manage the risks?
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