Immune debt: Recrudescence of disease and confirmation of a contested concept

1. Introduction

Over the last 3 years, the nightmarish COVID-19 pandemic imposed unprecedented non-pharmaceutical interventions (NPIs) which impacted the epidemiology of many other pediatric infectious diseases [1], [2]. Prolonged reduction of exposure to many viruses and bacteria resulted in a lack of immune stimulation against varied community-acquired pathogens, leading to expansion of the “naive” population to these pathogens and to the decline of herd immunity, making children more vulnerable to these infections [3]. In this context and in this journal, a year and a half ago our group put forward the concept of “immune debt”[3]. Briefly, after barrier measures were lifted, we raised concerns about the epidemiological rebound of many infectious diseases of varying severity and the occurrence of unpredictable epidemics throughout one year [3], [4]. Worldwide, many researchers published articles concurring with our concept of “immunity debt”, which is also called “immunity gap” [5], [6], [7], [8]. Unfortunately, due to possible misunderstanding and oversimplification of our concept, many controversies and polemics arose on social media and networks, and a backlash ensued.

The aim of this article is to highlight aspects of the concept that were not sufficiently understood by its detractors, to provide clarifications, and to deliver a brief overview of our innovative hypothesis.

2. Major clarifications

• -We fully agree that the NPIs in place to contain the COVID-19 pandemic were necessary, but are also convinced that like any therapeutic measure, they may have had unexpected consequences [9].
• -We never affirmed that NPIs would weaken the immune capacities of individuals or that lack of exposure to pathogens such as respiratory syncytial virus (RSV) and influenza could irrevocably damage the immune system. We simply suggested that due to a lack of pathogen exposure, NPIs could decrease some children’s adaptative immunity to specific pathogens.
• -From our standpoint $, immune debt should also be considered at the population level. If this winter, numerous infants in many countries are hospitalized for bronchiolitis, it is partly because the whole population, including adults, especially parents of very young infants, have become more susceptible to respiratory viruses (mainly RSV, viruses known for their limited and transient immunity despite iterative reinfections) leading to their increased circulation and transmission in the community. Furthermore, some mothers may have transmitted lower levels of RSV antibodies to their newborns, thereby reducing their protection [10].

3. Facts supporting our hypotheses

In France and in many other countries, the “immunity debt” has come due and is being to have been paid with interest [5], [6], [11], [12], [13], [14], [15]. Today, we are facing an unprecedented bronchiolitis outbreak in France with a higher and earlier (6-week) peak [16]. The intensity and the precocity of the epidemic lend credence to the immunity debt concept. The new epidemic pattern, which has entailed overload of hospital emergency services, wards and intensive care units, should have been anticipated by health authorities -- and requires urgent and specific appropriate responses [4], [17]. The NPIs targeting very young children should be quickly implemented for their protection and so as to counteract the consequences of the immune debt.

We recently summarized the relevant trends in a French community-acquired infection networks in a prospective multicentric surveillance study (PARI, Pediatric and Ambulatory Research in Infectious diseases) [14]. We showed that after having fallen in 2020, in 2021 the number of consultations for infectious diseases increased to a level never reached before [14]. Pediatric diseases such as enterovirus infections raise specific concerns, and we observed an unprecedentedly high peak in France in July 2021 [18], [19]. Similar findings were reported for otitis media and gastroenteritis. Once again, the intensity of these outbreaks underscores the relevance of the immunity debt concept [14].

Lastly, the increased number of antibiotic prescriptions in many European countries as well as the USA, Canada and Australia might be another indirect consequence of the “immunity debt” [20], [21], [22], [23]. Unfortunately, the increase was reported without any change in guidelines for pediatric antibiotic use and resulted in antibiotic shortages, particularly for amoxicillin [20], [21], [22], [24].

In England, where meningococcal B vaccination recommendation is limited to infants, an unusually sharp increase in invasive serogroup B meningococcal infections was reported in adolescents who had only been vaccinated against ACYW serotypes [24]. The number of cases exceeded the pre-pandemic number. The serogroup and age distribution suggested that ACWY meningococcal vaccination programmes in adolescents maintained low rates of group C, W, and Y disease due to herd immunity. By contrast, low immunity against group B strains in adolescents and young adults and high level of carriage and transmission of these strains resulted in the resurgence of invasive group B disease [24]. COVID-19 pandemic lockdowns reduced the opportunities for meningococcal exposure among adolescents and decreased carriage, which may have resulted in another ‘immunity debt’ in this population [24]. In the coming weeks or months, an increase in invasive bacterial infections is to be feared not only for invasive meningococcal diseases, but also for pneumococcal and even group A streptococcal (GAS) infections, which are also partially due to the resurgence of viral diseases in children [25]. In point of fact, the latest data from the UK Health Security Agency show a higher number of GAS infections, albeit without evidence that a new strain is circulating. The investigations presently underway have shown that the increase is most likely related to high amounts of circulating bacteria and social mixing [26]. Similarly in France, several invasive GAS infections have been reported in children under 10 years of age [27].

4. Conclusion

These findings buttress the general concept of “immunity debt”, which may be manifested at various levels, according to different pathogens and their ways iof transmission. Each country needs to strengthen its immunization program so as to limit the consequences of the immune debt and to improve infectious disease surveillance, the objective being to better anticipate future epidemics.

Authors’ contributions

RC and CL wrote the manuscript. All other authors revised and approved the manuscript.

Availability of data

No data.

Conflicts of interests

CL received personal fees and non-financial support from Pfizer and MSD outside the submitted work.

AR received non-financial support from Pfizer, and AstraZeneca, outside the submitted work.

FA received personal fees and non-financial support from Pfizer, GSK, MSD, and Sanofi, outside the submitted work.

NO declares no competing interests for this study.

EG declares no competing interests for this study.