About a third of the world is under lockdown or quarantine as a public health measure to slow the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). . Policymakers are increasingly pressured to articulate their rationale and strategies for exiting the lockdown .
The resurgence process is already beginning cautiously in Austria, Switzerland, Denmark, Wuhan and some US states. As the balance between further spread of the disease and the socioeconomic costs is debated, it is essential that those responsible for policymakers in all affected countries have the best possible data and knowledge to inform any course of action.
Strategies in several countries that aim to stagger return to work based on risk of disease severity and age do not take into account how to expose even lower risk people, such as young people without comorbidities, to the virus to increase Herd immunity can still cause a pandemic to spread .
The only selective pressure on SARS-CoV-2 is transmission: stop transmission and you stop the virus.
The key to a strategy out of lockdown apparently lies in increased testing and contact tracing, possible return-to-work permits based on immune status, 1 new or proposed therapeutics, 2 and, finally, vaccination3 , 4.
This approach is broadly sensitive, but immunology is a complex branch of molecular medicine and policymakers should be alerted to important aspects of immunology in relation to COVID-19.
| There is no certainty as to the immunological correlates of antiviral protection or the proportion of the population that should achieve them, making it impossible to identify a point when this level of immunity has been achieved. |
The current discussion, for example, addresses the notion that expanded antibody testing will determine who is immune, thus giving an indication of the degree of herd immunity and confirming who might re-enter the workforce.
There are questions that need to be addressed about the accuracy of the tests and the practicalities of implementing laboratory assays versus home -use assays.5
For any country contemplating these issues, another crucial question is how strong is the assumption that antibodies against the SARS-CoV-2 spike protein equate to functional protection?
Furthermore, if the presence of these antibodies is protective, how can one decide what proportion of the population requires these antibodies to mitigate subsequent waves of COVID-19 cases?
Any discussion should be informed by considering the correlates of protection . Initially proposed by Stanley Plotkin, 6, 7
Total measurable antibody is not exactly the same as protective virus-neutralizing antibody
This concept is based on the notion of quantifiable, empirically defined immune parameters that determine the achievement of protection against a given pathogen. Caution is needed because the measurable total antibody is not exactly the same as the protective virus-neutralizing antibody.
Additionally, studies in COVID-19 show that 10 to 20% of symptomatically infected people have little or no detectable antibodies.8
In some cases of COVID-19, low titers of virus-binding antibodies may correlate with a lethal or near-lethal infection , or with having had a mild infection with little antigenic stimulation. Importantly, scientists must not only identify correlates of protection, but also have a solid understanding of the correlates of progression to severe COVID-19, as knowledge of the latter will inform the former.
The route to certainty about the degree and nature of immunity required for protection will require evidence from formal testing using approaches such as titrated transfers of antibodies and T cells to define protection in non-human primate models, as used, for example, in studies of the Ebola virus.9
A study of SARS survivors showed that about 90% had functional virus-neutralizing antibodies and about 50% had strong T cell responses.10
These observations reinforce confidence in a simple view that most survivors of severe COVID-19 would be expected to have protective antibodies. One caveat is that most studies, whether of SARS survivors or COVID-19 patients, have focused on people who were hospitalized and had severe, symptomatic illness . Similar data are urgently needed for people with SARS-CoV-2 infection who have not been hospitalized .
How long is immunity to COVID-19 likely to last?
The best estimate comes from closely related coronaviruses and suggests that in people who had an antibody response, immunity may wane but is detectable more than 1 year after hospitalization.10.11.12
Obviously, longitudinal studies with a duration of just over 1 year are of little certainty given the possibility that there may be another wave of COVID-19 cases in 3 or 4 years. However, specific T cell immunity against Middle East respiratory syndrome coronavirus may be detectable for 4 years , considerably longer than antibody responses.
Some of the uncertainty about COVID-19 protective immunity could be addressed by monitoring the frequency of reinfection with SARS-CoV-2. Anecdotal reports of reinfection from China and South Korea should be viewed with caution because some people who appeared to have cleared SARS-CoV-2 infection and tested negative by PCR could have harbored persistent viruses . Virus sequencing studies will help resolve this issue, and in cases of confirmed reinfection, it will be important to understand whether reinfection correlates with lower immunity.
Policy briefs in the UK and other countries have rightly emphasized the imperative of collecting seroprevalence data.
This approach has sometimes been interpreted narrowly as testing that would allow people to return to work. However, seroprevalence data can show what proportion of a population has been exposed to and is potentially immune to the virus and is therefore completely different from the snapshot of people who accessed PCR testing.
How can you determine how much herd immunity is enough to mitigate subsequent substantial outbreaks of COVID-19?
This calculation depends on several variables,15 including the calculated basic reproduction number (R0), which is currently believed to be approximately 2 2 for SARS-CoV-2.16 Based on this estimated R0, the calculation of herd immunity suggests that at least 60% of the population would need protective immunity, either against natural infection or vaccination.17
This percentage increases if R0 has been underestimated .
Most of the available COVID-19 serological data comes from people who have been hospitalized with severe infection8, 18. In this group, around 90% develop IgG antibodies within the first 2 weeks of symptomatic infection and this aspect coincides with the disappearance of the virus18, which supports a causal relationship between these events.
However, a key question concerns antibodies in non-hospitalized individuals who have mild disease or no symptoms.
| Anecdotal results from community samples yield estimates of less than 10% of tested "controls" developing specific IgG antibodies. We expect larger seroprevalence data sets, but it seems likely that natural exposure during this pandemic may, in the short to medium term, not deliver the required level of herd immunity and there will be a substantial need for mass vaccination programs . |
There are more than 100 COVID-19 vaccine candidates in development, with a handful in Phase 1 trials, or soon to be, to evaluate safety and immunogenicity.
Vaccine candidates encompass various platforms that differ in the potency with which immunity is stimulated, the specific arsenal of immune mediators mobilized, the number of stimuli required, the durability of protection, and the ability to track production and supply chains3. , 4.
The safety evaluation of COVID-19 vaccine candidates must be of the highest rigor. Some characteristics of the immune response induced by infection, such as high concentrations of tumor necrosis factor and interleukin 6 , which could be provoked by some vaccine candidates, have been identified as biomarkers of severe outcomes 19.
Researchers should be commended for decades of iterative efforts, bringing us to a point where there are many vaccine candidates in development against a new virus first sequenced in January 2020. Delivering effective vaccines is not a competitive race to the finish line. final, but it is considered an evaluation of a safe, powerful and global response.
Few would disagree that science should guide the clinical therapeutic approach to an infected person. Science must also guide political decisions . Reliance on comprehensive seroprevalence data and a robust research-based understanding of correlates of protection will allow policy to be guided by safe, evidence-based assumptions about herd immunity, rather than optimistic assumptions.
