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The World Health Organization (WHO) with the support of Strategic Advisory Group of Experts (SAGE) on Immunization and its COVID-19 Vaccines Working Group, continues to review the emerging evidence on the increasing seroprevalence
rates against SARS-CoV-2 globally and the characteristics and potential benefits of hybrid immunity. This statement reflects the current understanding of hybrid immunity and highlights the gaps in evidence and potential implications for vaccination
schedules and strategies.

Definitions

The following definitions and terminology are used in this note:

• Infection-induced immunity is defined as the immune protection in an unvaccinated individual after one or more SARS-CoV-2 infections.
• Vaccine-induced immunity is defined as the immune protection in an individual who has not been previously infected with SARS-CoV-2 but has completed a primary series (currently one or two doses of EUL COVID-19 vaccine depending on
  the product) of any COVID-19 vaccine, or has also received a booster vaccination.
• Hybrid immunity is defined as the immune protection in individuals who have had one or more doses of a COVID-19 vaccine and experienced at least one SARS-CoV-2 infection before or after the initiation of vaccination.

In each case, the immune protection can be measured against different specific endpoints – infection (including viral load), disease (regardless of severity), or severe outcomes (hospitalisation, severe disease, or death) – and the level of protection
may vary according to endpoints. For each endpoint, the immune protection may differ by vaccine, time since vaccination or infection, by SARS-CoV-2 variants, and host-specific factors such as age and comorbidities.

Seroprevalence

Exposure to SARS-CoV-2 through infection or vaccination triggers the production of antibodies that can be readily measured in the blood (referred to as ‘seroconversion’). If the level of antibodies in the blood exceeds a pre-specified threshold,
the individual is said to be ‘seropositive’. This threshold can vary with the assay used, the target antigen being measured, and over time since exposure. The percentage of seropositive individuals in a population at a given timepoint
is referred to as the seroprevalence of SARS-CoV-2 in that population.

Inferring the level of population-level protection against infection and/or severe outcomes from seroprevalence estimates is challenging for several reasons. First, the amount of antibodies produced in an individual due to infection or vaccination, and
the waning of these over time, is determined by multiple factors such as age, the variant which caused infection, the severity of the infection, and vaccine product(s), among others. Therefore, seroprevalence estimates depend on survey design (e.g.
sampling frame) as well as on the epidemiological history of the population. Second, seroprevalence estimates are based only on measures of antibodies and do not incorporate measures of cell-mediated immunity, which is an important component of the
overall immune protection.

Delineating the degree of infection-induced, vaccine-induced, and hybrid immunity through seroprevalence estimates is similarly complex. The mechanism of exposure to the virus (infection or vaccination) and the vaccine product(s) mediate the immunological
response i.e., the kind of antibodies produced and type of cell-mediated immune response triggered. For instance, mRNA and adenovirus vector vaccines induce antibodies against SARS-CoV-2 spike protein; thus, a positive test for spike protein specific
IgM or IgG in individuals who have received these vaccines could indicate either prior infection or prior vaccination. To differentiate between the two, a nucleocapsid protein-based assay needs to be used; a positive nucleocapsid-protein assay indicates
prior infection. In contrast, inactivated SARS-CoV-2 vaccines elicit an immunological response to the spike and nucleocapsid protein; thus, in individuals who have received an inactivated vaccine, a positive result in a test for spike protein specific
IgM or IgG or a test that specifically evaluates IgM or IgG to the nucleocapsid protein could indicate either prior infection or prior vaccination. Currently available SARS-CoV-2 antibody tests used in serosurveys assess levels of IgM and/or IgG to
the spike or the nucleocapsid protein. The vast majority of countries have used a combination of mRNA, viral-vectored and inactivated vaccine products, which makes it difficult to distinguish between the degree of infection- versus vaccine-induced
immunity in a population. Moreover, even in settings in which predominantly mRNA vaccines were used, a positive test for anti-nucleocapsid antibodies cannot identify episodes of reinfection, which is an important consideration in assessing levels
of hybrid immunity.

Thus, it is difficult to directly infer the degree of population-level protection against infection, and to disentangle the levels of infection- or vaccine-induced and hybrid immunity from

seroprevalence studies. Notwithstanding, both infection- and vaccine-induced immunity confer high protection against severe disease, with hybrid immunity being superior, as outlined below.

Current situation: global seroprevalence trends

According to the most recent estimates by the WHO UNITY Studies Collaborator Group shared with SAGE, the percentage of seropositive individuals increased in all regions during 2021, globally rising from 16% in February to 67% by October 2021 ¹ . Seroprevalence varied across countries as well as sub-nationally including across sub-populations within countries during this period. Seroprevalence rates also varied by age, with lower rates reported for the youngest (0-9) and oldest age groups
(60+) compared to adults aged 20-29 years in studies up to end of 2021¹. In most low- and middle-income countries, the rise in seroprevalence in this period has been driven by an increase in infections rather than vaccination, given
the very low vaccination rates through the end of 2021.

The Omicron variant (BA.1 and then BA.2), which emerged in November 2021, is highly transmissible and has become dominant in all regions of the world, rapidly replacing the previously circulating variants. New sub-lineages of Omicron are emerging, such as BA.3, BA.4 and BA.5. Due to a steep rise in the number of infections in many countries following the emergence of Omicron and increasing vaccine coverage, both vaccine- and infection-induced population seroprevalence levels are expected to have
increased substantially since October 2021, albeit with sustained regional and sub-population variations. The widespread exposure to Omicron and variable vaccination coverage across and within countries has resulted in a complex population-based immunity
landscape.

Evidence for infection-induced, vaccine-induced, and hybrid immune protection

Protection against infection and mild symptomatic disease.

A previous SARS-CoV-2 infection provides high protection against reinfection with variants of concern (VOCs) such as Alpha and Delta², which have limited immune escape characteristics. The duration of infection-induced protection depends on
a range of host-specific factors including the severity of the immunizing infection³. Generally, protective immunity against infection and mild disease has been observed to persist for 10-12 months post-infection for pre-Omicron VOC⁴.
A SARS-CoV-2 infection has also been found to induce durable cell-mediated immunity for at least 6-8 months⁵, although the evidence for this is from pre-Omicron VOCs. Data for duration of protection beyond these time frames are still being
collected in prospective cohort studies.

Infection-induced immunity confers significantly less protection against Omicron than against non-Omicron VOC six or more months after a previous infection^6–8. The durability and breadth of immunity after infection with Omicron
in unvaccinated individuals has not yet been determined.

Vaccine-induced immunity following a primary vaccine series is modest against infection due to Omicron in the months after vaccination, and wanes significantly over time⁶. Vaccine-induced immunity against Omicron-related mild symptomatic disease,
asymptomatic infection, and viral shedding is also modest and short-lived even following a booster dose⁹.

The majority of studies have found that the protection conferred by hybrid immunity against infection and mild symptomatic disease is similar, or modestly better than that by infection-induced or vaccine-induced immunity alone^6–8. Compared
with infection-induced immunity, hybrid immunity from two or three exposures to the antigen (infection with pre-Omicron VOC or Omicron and one or two doses) improve immune protection against symptomatic infection due to Omicron^7,8. The
immune protection after two doses (with a prior infection) waned 10-19 weeks after the second dose but was restored after a booster dose^7,8. However, the duration of additional protection achieved through boosters was variable^6–8,10.

Protection against disease, and severe outcomes including death.

Infection-induced immunity was found to provide strong protection against severe disease caused by pre-Omicron VOC up to 9-12 months post infection¹¹, with some waning observed in this period. Infection-induced protective immunity against disease
and severe outcomes wanes faster against VOCs, especially against Omicron^4,7.

Currently available data from emergency-use listed COVID-19 vaccines show that vaccines provide higher levels of protection than SARS-CoV-2 infection against severe disease outcomes, with modest waning in the 6 months following completion of primary vaccine
series¹². Further, they continue to protect against severe disease, hospitalizations and death due to Omicron, albeit to a lesser degree compared with other VOC¹³. The level of initial protection achieved and the degree of waning
of vaccine effectiveness may differ depending on the VOC circulating in the population. The extent of waning may further depend upon the vaccine product(s) in use, and the target population (e.g., older adults, immunocompromised persons). Vaccine-induced
protection against symptomatic disease, including severe disease, is enhanced by booster doses^13,14.

Hybrid immunity resulting from three or more exposures to the virus antigen (i.e., one or more exposures from vaccination and one or more from SARS-CoV-2 infections before or after vaccination) may provide superior protection (as measured by neutralization
capacity) against VOCs, including Omicron, compared with two doses of vaccination, or previous SARS-CoV-2 infection without vaccination¹⁵. Waning of hybrid immunity, particularly due to Omicron infections is not yet characterized in magnitude
or duration. More data are needed for a precise quantification of the immune protection from hybrid immunity compared with vaccine-induced immunity normalised for the same antigen exposure.

Policy implications of high seroprevalence levels and hybrid immunity

The need for, and optimal timing of, the primary vaccination series and booster doses may differ according to whether individuals have had a SARS-CoV-2 infection. At a population level, the number of doses and inter-dose interval, including for booster
doses, may differ between settings with high and lower seroprevalence resulting from infection-induced immunity¹⁶. These considerations may be particularly important in identifying simplified vaccination schedule in lower-priority
use groups identified in the WHO Roadmap prioritizing use of COVID-19 vaccines¹⁶.

Any policy regarding the vaccination of lower priority use groups should involve clear specification of the value of vaccination under consideration and multiple trade-offs, with seroprevalence in these groups representing one of the factors to be considered
in the future. For instance, a modelling study in Kenya estimated that vaccination of young adults may not be cost-effective in a high seroprevalence setting¹⁷. At the same time, evidence from observational studies suggests that vaccination
can reduce incidence of post COVID condition¹⁸. Prevention of mild disease, indirect impact on transmission, and reduction of incidence of post COVID condition can provide a strong rationale for vaccinating low priority use groups
irrespective of previous exposure.

The WHO Roadmap for prioritizing use of COVID-19 vaccines sets a goal of achieving very high vaccination coverage rates in the highest and high priority-use groups. Every effort should be made to achieve high coverage with primary series and boosters
in the most at-risk populations, irrespective of the infection-induced seroprevalence in that country . In light of existing evidence gaps, and heterogeneity of seroprevalence across population groups, the WHO Roadmap is currently not considering
infection-induced immunity in its prioritization scenarios or dosing schedule.

Evidence gaps

While the overall evidence suggests that hybrid immunity offers superior protection against severe outcomes due to COVID-19 compared to infection-induced or vaccine-induced immunity alone, it is unclear whether this protection will persist with new variants.
For instance, evolving evidence suggests that an Omicron BA.1 infection offers only limited protection against symptomatic disease caused by the emerging sub-lineages of Omicron (BA.4 and BA.5)¹⁹.

Moreover, there are crucial gaps in our current understanding of this complex issue. The duration of protection provided by hybrid immunity has not yet been determined, particularly that induced by Omicron infections. Both the quality and durability of
hybrid immunity are likely to vary across age-groups and in individuals with underlying medical conditions including immune-compromising conditions. Further, these differences arise from a complex interplay of the SARS-CoV-2 variants with which individuals
were infected, the vaccine product(s) in use, the interval between doses, and the time between vaccination and infection. These variations should be studied to further our understanding on how and when to use booster doses of vaccine to optimize vaccination
strategies, including dosing schedule.

As of now, these is little to no data on the protective immunity in unvaccinated individuals who have experienced more than one SARS-CoV-2 infection. The durability and breadth of immune protection due to reduced doses (e.g. a single dose) of vaccines
in conjunction with infection-induced immunity also remains under-studied. Assessment of the level of protection afforded by hybrid immunity thus generated is critical to inform optimal vaccination schedule, especially for in low-priority use groups,
in light of increasing seroprevalence in these groups.

Conclusion

COVID-19 remains a severe threat to global health security and public health. The emergence of VOCs poses formidable challenges for global recovery from pandemic through immune evasion, increased transmissibility, or enhanced severity. The evolution of
the pandemic remains unpredictable. Vaccination against COVID-19 reduces the risk of severe morbidity, and curtails the burden on health systems by protecting against hospitalization and death. Moreover, hybrid immunity confers improved protection
compared to infection-induced immunity alone. Therefore, in line with the WHO SAGE Roadmap for prioritizing use of COVID-19 vaccines, achieving high primary vaccine series coverage in individuals in the highest and high-risk groups remains the
foremost priority, irrespective of their infection history. Countries and implementing partners should emphasize the urgent need to fulfil this primary objective by calling for vaccination of all healthcare workers, immunocompromised individuals,
and older persons. Booster doses are associated with enhanced protection against Omicron; highest and high-priority use groups should similarly be prioritised for these.

With more evidence, integrating infection and vaccination-induced immunity into vaccination strategies and/or schedules may provide gains through simplified and/or more effective immunization schedules in countries or communities that have already experienced
high levels of community transmission. However, basing national vaccination policies on seroprevalence rates poses several challenges. Seroprevalence rates observed in population-based studies may not be representative of the entire population or
certain subpopulations and age groups, and may also differ by factors such as urban versus rural settings. Moreover, hybrid immunity, although superior to infection- or vaccine induced immunity alone, depends on a number of factors in complex and
interrelated ways.

Meanwhile, WHO reiterates the need for accruing consistent population representative data over time to further improve our understanding of waning of seroprevalence and hybrid immunity. In particular, seroprevalence studies are needed in specific
at-risk populations such as older age groups which may inform vaccine priorities and targeted efforts in the future.

An improved understanding of hybrid immunity will contribute to evidence-based decisions on the need for additional COVID-19 vaccine doses to populations. When more evidence is available, advice on if and how hybrid immunity should be considered in national
vaccination policies will be updated.

References:

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3. Chia, W. N. et al. Dynamics of SARS-CoV-2 neutralising antibody responses and duration of immunity: a longitudinal study. Lancet Microbe 2, e240–e249 (2021).
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