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The Lancet: Most comprehensive study to date provides evidence on natural immunity protection by COVID-19 variant and how protection fades over time
- Largest review and meta-analysis assessing the extent of protection following COVID-19 infection by variant and how durable that protection is against different variants, including 65 studies from 19 countries.
- For people who have been infected with COVID-19 at least once before, natural immunity against severe disease (hospitalisation and death) was strong and long-lasting for all variants (88% or greater at 10 months post infection).
- Past infection with pre-Omicron variants provided substantially reduced natural immunity protection against reinfection with Omicron BA.1 (36% at 10 months after infection).
- The researchers say we should recognise the natural immunity in people who have recently been infected with COVID-19, but warn that their findings should not discourage vaccination because it is the safest way to acquire immunity.
For someone previously infected with COVID-19, their risk of hospitalization or death is 88% lower for at least 10 months compared to those who had not been previously infected, according to a systematic review and meta-analysis published in The Lancet.
The analysis also suggests that the level and duration of protection against reinfection, symptomatic disease and severe illness is at least on a par with that provided by two doses of the mRNA vaccines (Moderna, Pfizer-BioNtech) for ancestral, Alpha, Delta and Omicron BA.1 variants. The study did not include data on infection from Omicron XBB and its sublineages.
“Vaccination is the safest way to acquire immunity, whereas acquiring natural immunity must be weighed against the risks of severe illness and death associated with the initial infection,” says lead author Dr Stephen Lim from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington’s School of Medicine, USA. [1]
As IHME co-author Dr Caroline Stein explains: “Vaccines continue to be important for everyone in order to protect high-risk populations such as those who are over 60 years of age and those with comorbidities. This also includes populations that have not previously been infected and unvaccinated groups, as well as those who were infected or received their last vaccine dose more than six months ago. Decision makers should take both natural immunity and vaccination status into consideration to obtain a full picture of an individual’s immunity profile.” [1]
Since January 2021, several studies and reviews have reported the effectiveness of past COVID-19 infection in reducing the risk of reinfection and how immunity wanes over time. But none has comprehensively assessed how long the protection after natural infection will last and how durable that protection will be against different variants.
To provide more evidence, the researchers conducted a review and meta-analysis of all previous studies that compared the reduction in risk of COVID-19 among non-vaccinated individuals against a SARS-CoV-2 reinfection to non-vaccinated individuals without a previous infection up to September 2022.
It included 65 studies from 19 countries [2] and evaluates the effectiveness of past infection by outcome (infection, symptomatic disease, and severe disease), variant, and time since infection. Studies examining natural immunity in combination with vaccination (i.e., hybrid immunity) were excluded from the analyses.
Immunity fades over time
Analysis of data from 21 studies reporting on time since infection from a pre-Omicron variant estimated that protection against reinfection from a pre-Omicron variant was about 85% at one month—and this fell to about 79% at 10 months. Protection from a pre-Omicron variant infection against reinfection from the Omicron BA.1 variant was lower (74% at one month) and declined more rapidly to 36% at around 10 months.
Nevertheless, analysis of five studies reporting on severe disease (hospitalisation and death) found that protection remained universally high for 10 months: 90% for ancestral, Alpha, and Delta, and 88% for Omicron BA.1.
Six studies evaluating protection against Omicron sub-lineages specifically (BA.2 and BA.4/BA.5) suggested significantly reduced protection when the prior infection was pre-Omicron variant. But when the past infection was Omicron, protection was maintained at a higher level.
“The weaker cross-variant immunity with the Omicron variant and its sub-lineages reflects the mutations they have that make them escape built-up immunity more easily than other variants,” says IHME co-author Dr Hasan Nassereldine. “The limited data we have on natural immunity protection from the Omicron variant and its sub-lineages underscores the importance of continued assessment, particularly since they are estimated to have infected 46% of the global population between November 2021 and June 2022. Further research is also needed to assess the natural immunity of emerging variants and to examine the protection provided by combinations of vaccination and natural infection.” [1]
The researchers note some limitations of their study, cautioning that the number of studies examining the Omicron BA.1 variant and its sub-lineages and the number from Africa was generally limited. In addition, only limited data were available beyond 10 months after the initial infection. They also note that some information, such as past infection status and hospital admissions, was measured differently or incomplete, and could bias the estimate of protection.
Writing in a linked Comment, Professor Cheryl Cohen, National Institute for Communicable Diseases, South Africa, who was not involved in the study, says, “The high and sustained levels of protection conferred by previous infection against severe disease have important implications for COVID-19 vaccine policy. By September, 2021, global SARS oV-2 seroprevalence was estimated at 59%, with substantial variation in the proportion of immunity induced by infection or vaccination in different settings. Seroprevalence in Africa was estimated at 87% in December, 2021, largely as a result of infection. High levels of immunity are an important contributor to the lower levels of severity observed with infection caused by emerging Omicron subvariants. As SARS-CoV-2 epidemiology shifts to more stable circulation patterns in the context of high levels of immunity, studies of the burden and cost of SARS-CoV-2 infection and risk groups for severe disease are needed to guide rational vaccination policy and decisions around prioritisation in relation to other vaccine preventable diseases.”
Expert Reaction
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
Dr Deborah Burnett is a Group Leader at the Garvan Institute of Medical Research and Senior Lecturer at St Vincent’s Clinical School, UNSW
When most people are exposed to the immune targets of COVID-19, through either natural infection or vaccination, their immune system will mount a protective response. This immune response consists of a variety of protective immune cells This includes B cells, which make antibodies, as well as T cells and other immune types. Some of these cell types are important in reducing your risk of severe disease, while other cell types like B cells, which make antibodies, are critical for your ability to protect yourself from becoming re-infected with the virus.
The good news is some immune cells that are important for protection against severe disease can cross-react between multiple different strains of the virus. This means that if you have been vaccinated against COVID-19 or recovered from COVID-19 infection, when you are re-infected, even with a different strain, your risk of hospitalisation and severe disease is greatly reduced. This meta-analysis, pooling together the previous findings from many others in the field, highlights that people who have been previously infected with or vaccinated against COVID-19 show a greatly reduced risk of severe disease when re-infected with the virus, even if their secondary infection is a different strain from their original infection.
However, unfortunately, this analysis also highlights that following COVID-19 infection or vaccination, your risk of becoming re-infected with later variants, such as the Omicron variant, is only partially prevented. Research by our team and others has shown that one of the reasons this occurs is because the antibodies your immune system makes on exposure to COVID-19 target sites that do not show good protection against later COVID-19 variants.
Unfortunately, most of the antibodies you make following infection or vaccination, target regions of the virus that the virus can easily mutate. This means that later variants of COVID-19 can escape these antibodies.
The fact that your risk of severe disease is greatly reduced on re-infection with COVID-19 is great news. However, the ongoing spreading of the virus is still problematic as it still leaves vulnerable populations at risk and it allows the virus to continue and mutate into newer variants.
Associate Professor Vinod Balasubramaniam is a Molecular Virologist and the Leader of the Infection and Immunity Research Strength from the Jeffrey Cheah School of Medicine & Health Sciences at Monash University in Malaysia^unescape^unescape
Multiple studies in different settings have consistently shown that infection with SARS-CoV-2 and vaccination each result in a low risk of subsequent infection with antigenically similar variants for at least 6 months.
Results from this systematic review and meta-analysis shows high levels of protection against re-infection for ancestral, Alpha, and Delta variants for all major outcomes. Although there is significantly reduced protection against re-infection from the Omicron BA.1 variant, levels of protection against severe disease remained high. These results provide information that can be used to tailor guidance on the number and timing of SARS-CoV-2 vaccinations.
At the public health level, these findings can be combined with data on local infection prevalence, vaccination rates, and their timing. Interestingly, the level of protection from past infection by variant and over time is equivalent to that provided by two-dose mRNA vaccines has important implications for guidance regarding the timing of vaccine doses, including boosters.
This finding also has important implications for the design of policies that restrict access to travel or venues or require vaccination for workers, where those with a documented infection should be treated similarly to those who have been fully vaccinated with high-quality vaccines.
Professor Paul Griffin is the Director of Infectious Diseases at Mater Health Services and the Head of the Mater Clinical Unit for the University of Queensland School of Medicine
A greater understanding of immunity against COVID-19 both from infection and vaccination is still needed so this work seems to be a valuable addition to existing knowledge particularly given it’s the largest meta-analysis conducted to date. The situation with COVID-19 has continued to change at a rapid pace so looking at protection against different variants is very helpful, although this study included up to the BA.1 subvariant of Omicron and there have been many subsequent subvariants since.
This study indicates that protection from hospitalisation and death from a new COVID-19 infection is 88.9% lower even after 40 weeks in those previously infected with Omicron BA.1 compared to those who have not been infected. Protection was higher for variants prior to Omicron, i.e. ancestral, Alpha and Delta. While direct comparisons have not been made in this study, this would be similar or perhaps a little less than we could expect to see from vaccination against these more severe endpoints.
The obvious difference to keep in mind between protection from vaccination versus that provided by infection is that infection carries with it the risk of disease (including severe disease in a proportion) whereas vaccination does not. It is also important to consider that some of the challenges we face with the longevity of protection from vaccination including for example waning over time and immune evasion also apply to protection generated by infection.
Some of the challenges to also consider with natural immunity were evident in this study by the protection provided by natural infection being substantially lower for the Omicron variant BA.1 than pre-Omicron variants and that it also declined more rapidly than protection against previous variants.
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