Vaccine-induced strain replacement: theory and real-life implications

Abstract

The value of preventive medicine is superior to treatment with vaccinations occupying high priority. Nevertheless, heavy pressure has started to form in regard to strains not included in vaccines contributing to the changing epidemiology of pathogen subtypes leading to ‘vaccine-induced strain replacement’. Among other mechanisms, increasing fitness of nonvaccine strains and metabolic shifts in the subtypes have been described. Classical examples include pneumococcal infections and viral diseases, such as the human papilloma virus. Recently, it has been described in SARS-CoV-2, leading to the emergence of new subtypes, such as Omicron and Delta variants. The phenomenon has also been reported in Mycobacterium tuberculosis, Neisseria meningitidis and rotavirus. This study addresses the concepts, examples and implications of this phenomenon.

Plain language summary

Article Highlights.

• The phenomenon of ‘vaccine-induced pathogen strain replacement’ is of great importance and associated with changes in epidemiology of various infectious agents.

• Among other pathogens reported to show the discussed phenomenon, S. pneumoniae, human papillomavirus, Haemophilus influenzae are discussed in our paper.

• The recent SARS-CoV-2 virus responsible for the COVID-19 pandemic has been correlated to the vaccine-induced pathogen strain replacement.

Potential mechanisms involved in vaccine-induced pathogen strain replacement

• Several mechanisms have been proposed to explain vaccine-induced pathogen strain replacement.

• Different efficacy of the used vaccines, beside metabolic shifts seen in different pathogenic strains are addressed.

Implications of vaccine-induced pathogen replacement phenomenon

• Increase numbers of nontargeted pathogens is of great epidemiological and clinical value.

• The phenomenon was linked to multidrug-resistant strains of bacteria such as MRSA.

Conclusion

• Changing epidemiology of strains necessitates continuous surveillance.

• From clinical point of view, acquaintance with vaccine-induced pathogen replacement phenomenon is of paramount importance.

• Vaccine design and related epidemiological impact should be addressed based, among other aspects, to the described phenomenon.

1. Background

Vaccines have contributed to a drastic fall in morbidity and mortality related to infectious agents in recent decades, which has made them fundamental players in preventive medicine. Mass vaccination worldwide has resulted in the eradication of devastating and lethal infections such as smallpox and rinderpest [1,2]. While the last two infectious diseases are considered to be eradicated, vaccines have played a crucial role in nearly eliminating other infections, such as poliovirus [3,4]. The evolutionary trajectories of pathogens are influenced by natural selection at multiple levels. For instance, pathogens engage in competitive interactions through two main means, either by dominating individual hosts at the within-host level or by spreading to a greater number of hosts at the between-host level [5]. At the within-host level, strain replacement occurs when a new strain substitutes for the one that initially infects a host without any recovery period [6,7]. In turn, at the between-host level, strain replacement occurs when the prevalence of a dominant strain diminishes, whereas another rare strain becomes more prevalent. In particular, the immune system has been shown to exert selective pressures on pathogen communities, whereas the introduction of vaccines alters selection dynamics by targeting specific pathogen variants. The resulting selective pressure enables nonvaccine strains to proliferate and therefore become more prevalent in the population. This phenomenon is recognized as the ‘vaccine-induced pathogen strain replacement’. Strain replacement has been documented in numerous infections and infectious agents. The following pathogens (bacteria and viruses) were identified.

1.1. Streptococcus pneumoniae

As a common pathogen of pneumonia and meningitis, Streptococcus pneumoniae (S. pneumoniae) produces over 100 antigenic types of capsular polysaccharides (CPSs), which are categorized based on distinct glycan compositions and linkages defining each serotype [8]. The polysaccharide capsule plays a crucial role in the bacterial ability to evade host immune responses and determines the strains serological identity of strains. Among these, 23 serotypes account for 80–90% of all of the invasive pneumococcal infections worldwide [9]. Approximately 20 years ago, pneumococcal pneumonia resulted in an estimated 1.8 million deaths in children under 5 years old worldwide [10]. The widespread use of pneumococcal conjugate vaccines (PCVs) has led to a decline in the prevalence of targeted strains. Furthermore, following the integration of routine pediatric vaccinations, a further reduction in pneumococcal infections attributable to vaccine-type pneumococci has been observed [11,12]. PCVs contain polysaccharides of various serotypes of S. pneumoniae serotypes that are conjugated to a carrier protein (generally either tetanus toxoid or diphtheria toxoid). The carrier protein is believed to stimulate stronger immune responses against vaccines [13]. PCV7 targets seven specific serotypes of S. pneumoniae (4, 6B, 9V, 14, 18C, 19F and 23F), referred to as ‘vaccine types’. In recent years, PCV10, PCV13, PCV15 and PCV20 have been introduced with expanded coverage (1, 2, 3, 5, 6A, 7F, 9N, 10A, 11A, 12F, 15B, 19A and 33F) [9]. Interestingly, PCV7 not only minimized disease incidence in vaccinated children, but also demonstrated a herd immunity effect among non-vaccinated groups, leading to widespread public health benefits. Nevertheless, among immunocompromised patients, those with HIV infection, diabetes, or chronic obstructive pulmonary disease, a higher proportion of episodes of invasive pneumococcal disease were attributed to non-PCV7 serotypes when compared to cases caused by the same serotypes among other patients [14].

In contrast, vaccination with PCV and subsequent mucosal immunity creates an ecological niche for nonvaccine serotypes [15,16]. In response to the evolving pneumococcal landscape after the introduction of PCV7, the emergence of nonvaccine types (NVTs) among asymptomatic carriers has been observed and they could be categorized under ‘vaccine-induced strain replacement’. This phenomenon is characterized by an increased prevalence of NVTs in the nasopharynx following the introduction of vaccine. For instance, after the commencement of universal vaccination with PCV7 in USA, S. pneumoniae type 19A, which is not covered by PCV7, became the predominant cause of pneumococcal disease in both children and adults [17,18]. Similarly, subsequent to the introduction of PCV13, numerous other serotypes, including 23B, 15BC, 19A, 15A, 35B and 15BC, have been shown to notably increase in prevalence [19–22]. This trend persists even with the emergence of recently developed higher-valency conjugate vaccines, such as PCV15 and PCV20. Although there has been a modest increase in the reported diseases associated with NVTs in many countries such as France, strain replacement has the potential to attenuate the overall public health impact of the vaccine [23].

Given the changing pneumococcal population dynamics, particularly the potential effects of serotype replacement, the widespread adoption of conjugate vaccines in new settings warrants the careful monitoring of the disease burden. This vigilance is essential to assess both the immediate and long-term consequences of mass vaccination in each region where the vaccine was introduced. This underscores the significance of tracking the pneumococcal strains that are emerging to replace vaccine types in each region or country. Such monitoring is pivotal for determining the necessity of upgrading to a pneumococcal vaccine with broader coverage.

1.2. Human papillomavirus

Human papillomavirus (HPV) is a sexually transmitted virus which is prevalent. Most patients with HPV infections are asymptomatic. However, resistant infections involving high-risk (oncogenic) HPV strains can contribute to the onset of cervical, anal, penile, vaginal, vulvar, and oropharyngeal cancers, which often occur several decades later [24]. Interestingly, HPV does not possess surface proteins that would allow traditional serotyping. Instead, HPV types are categorized primarily through DNA sequencing and are numbered based on the order of their discovery. Each HPV type has a distinct DNA sequence, particularly within the L1 gene region, which encodes the major capsid protein [25]. Sequencing of this region has allowed researchers to identify and differentiate different HPV types. Notably, nearly 70% of cervical cancers are related to infections with HPV 16 and 18 types [26]. Moreover, infections involving other high-risk HPV types, namely 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59, contribute to almost 30% of cervical cancer cases [27].

There are currently three licensed HPV vaccines available, bivalent (Cervarix, GSK, Rixensart, Belgium), quadrivalent (Merck, Sharp & Dome [Merck & Co, Whitehouse Station, NJ, USA]), and nonavalent (Merck, Sharp & Dome [Merck & Co, NJ, USA]). Analyses of the effectiveness of bivalent, quadrivalent and nonavalent vaccines targeting HPV 16/18 indicated comparable efficacy among the vaccines [28]. Nevertheless, the nonavalent vaccine offers supplementary safeguarding against HPV 31/33/45/52/58. In addition, vaccines contain virus-like particles (VLPs) composed of self-assembled L1 proteins derived from the major capsid of HPV, which resemble the structure of authentic virions. These VLPs lack viral DNA, rendering them noninfectious, but they are capable of eliciting an immune response.

Since the introduction of the HPV vaccine, protection has been provided against certain HPV types (6, 11, 16, 18, 31, 33, 45, 52, 58). However, certain mathematical models have highlighted the increased prevalence of nonvaccine HPV types in the post-vaccine era. Vaccine-induced strain replacement dynamics of HPV were investigated using a mathematical model that suggested a potential increase in nonvaccine high-risk HPV types following vaccination. Briefly, HPV types have been categorized into different phylogenetic clades, where cross-immunity may occur; however, the findings of a study regarding delayed cross-immunity impact on the odds ratios (ORs) of multiple HPV infections and their implications on vaccination efficacy were not clearly stated [29]. The same study also reevaluated epidemiological data regarding HPV infections and assessed the impact of cross-immunity on the prevalence of multiple HPV infections. Modeling analysis predicted that the removal of vaccine-targeted HPV types, such as 16 and 18, though vaccination could result in type replacement, wherein nontargeted high-risk HPV types, including 31, 33, 45, 52 and 58, were found to be increased in prevalence filling the ecological niche left by the eliminated strains. Although the article acknowledges that these types may have different carcinogenic potentials when compared to vaccine-targeted strains, such as HPV 16 and 18, the increased prevalence of nontargeted types is implicated in cervical cancer risk and public health strategies. Another study highlighted the potential impact of strain replacement due to HPV vaccination using a susceptible, infected and recovered (SIR) model [27]. In this scenario, nontargeted HPV types proliferate, albeit with a lower carcinogenicity. Together, these aforementioned findings prompt serious consideration of the long-term implications and effectiveness of HPV vaccination strategies.

1.3. Haemophilus influenzae

Haemophilus Influenzae (Hi) strains are classified based on the presence of a polysaccharide capsule, with capsulated strains, particularly type b (Hib) strains, being more invasive. In the unprotected populations receiving conjugated Hib vaccines, Hib is the most significant cause of invasive Hi infections, primarily affecting infants and young children [30]. Hi infections lead to acute pyogenic infections, including meningitis, epiglottitis, cellulitis and bacteremia [31]. Before effective vaccination became available, Hib and Streptococcus pneumoniae were the primary causes of childhood community-acquired pneumonia. Moreover, Hib infections were the leading cause of bacterial meningitis in children before the development of effective vaccines [32]. In contrast, non-capsulated Hi (ncHi) strains are associated with other infections such as otitis media in children and bronchopneumonia in the elderly, as well as exacerbations of chronic bronchitis in vulnerable populations (immunodeficiency and chronic underlying chest disease) [31].

Various types of Hi vaccines are available, including conjugate and polysaccharide vaccines. Conjugate vaccines, such as the Hib vaccine, comprise the Hib polysaccharide antigen coupled with a carrier protein that amplifies the immune response, particularly in infants. The inclusion of a carrier protein facilitates the activation of T-cell-dependent immune reactions, culminating in the generation of high-affinity antibodies and immunological memory [33]. In contrast, polysaccharide vaccines contain purified capsular polysaccharides from bacteria but lack carrier protein elements. While effective in older children and adults, these vaccines have demonstrated reduced immunogenicity in infants and young children because of their inability to elicit T-cell-dependent immune responses. Following the introduction of the first Hib vaccine, the prevalence of Hib-associated diseases showed a remarkable decrease (82%) within 6 years [34]. However, epidemiological studies conducted between 1996 and 2010 revealed an unexpected increase in the incidence of invasive disease due to non-Hib strains in children, specifically serotype f and non-typeable Hi, following the introduction of the Hib vaccine [32,35]. After the introduction of the conjugate Hib vaccine, non-capsulated Hi (ncHi) infections increased. This finding primarily pertains to adults, where invasive Hib infections in unimmunized adults decreased after the implementation of Hib immunization in children. However, the overall rate of invasive Hi disease in adults has increased [31]. Despite their relatively low incidence, accounting for nonvaccine Hi strains remains pivotal for shaping health policies and also fostering ongoing surveillance initiatives.

1.4. Bordetella pertussis

Bordetella pertussis was a significant childhood illness with high mortality rates until the invention of the pertussis vaccine in the 1940s. Pertussis vaccines were first developed as whole-cell vaccines containing inactivated whole cells of B. pertussis. These vaccines are highly effective in preventing severe disease but they were found to be associated with a higher incidence of local and systemic side effects, such as fever, fussiness and swelling at the injection site. Acellular pertussis (aP) vaccines have been developed to address safety concerns, while maintaining efficacy. Acellular vaccines contain purified B. pertussis components, primarily pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN) and fimbriae (FIM). These components are either chemically inactivated or genetically detoxified in order to render them nontoxic while retaining their immunogenic properties. With advancements in the pertussis vaccine, the vaccination efforts have resulted in a significant reduction of over 90% in pertussis cases compared to the pre-vaccination era. Nevertheless, despite sustained high vaccination coverage, pertussis has persisted, exhibiting endemic patterns with recurring epidemic peaks every 3–5 years, especially in adolescents and young adults since the early 1980s [36]. The shift in pertussis epidemiology during this period raises questions about the possible causes. Issues related to the diagnosis and reporting of the disease have also been highlighted. An additional factor to consider is the potential weakening of the vaccine-induced immunity in vaccinated individuals. Of significance, changes in the virulence or vaccine resistance of the circulating B. pertussis species have been postulated [37]. Actually, B. pertussis has shown wide variations in its antigenic structure, contributing to newly emerging strains not included in the vaccines available. Importantly, the observed changes were found to be attributed to the pertussis toxin (PT) gene named ptxP [38]. ptxP is believed to be responsible for the resurgence of pertussis. Furthermore, studies from the Netherlands have demonstrated differences among B. pertussis genetic subtypes between the pre- and post-vaccination eras, but the precise role of vaccination in subtype selection remains unclear [39]. This was reported in a recent paper illustrating the impact of shifting from whole-cell to acellular vaccines and its correlation with the emergence of novel strains not included in the vaccine [40].

A significant shift in the population of B. pertussis over the years, involving strain characterization through serotype, prn type and pulsed-field gel electrophoresis (PFGE), has been reported. Accumulating data suggest that changes in the etiological agent may contribute to the resurgence of pertussis in countries with high vaccination rates. Notably, persistent PFGE profiles clustered together, indicating common properties of longitudinal transmission [41]. While the prevalence of certain PFGE subtypes decreased, contemporary isolates displayed higher diversity, possibly due to the increased recovery of isolates. These studies have also underscored the impact of vaccination on B. pertussis dynamics, with shifts in prevalence corresponding to changes in vaccination policies [37]. Understanding the natural history of the population of B. pertussis is important in regard to interpreting historical and recent pertussis epidemiology, and also establishing a foundation for recognizing and addressing current and future trends, especially those linked to prevention strategies. Current studies recommend periodic testing of the potency of existing pertussis vaccines against the rising B. pertussis mutants [42].

1.5. SARS-CoV-2

During the pandemic of COVID-19, and following the mass vaccination against SARS-CoV-2, the virus has shown numerous variations under the pressure of vaccination and herd immunity. Unsurprisingly, recent studies have revealed a global trend toward strain replacement in circulating SARS-CoV-2 variants [43,44], notably with the rapid displacement of the Delta variant by Omicron [45,46]. Therefore, the World Health Organization has established a system for naming and classifying SARS-CoV-2 variants based on their genetic characteristics. Accordingly, variants were categorized based on their potential impact on public health. Factors considered in the classification include increased transmissibility; more severe disease; reduced effectiveness of diagnostics, vaccines, therapeutics or other public health measures; and the potential for immune evasion [47]. Interestingly, an Omicron surge occurred amid the widespread vaccination campaigns taking place, prompting speculation regarding vaccine-induced strain replacement. In addition, the Omicron variant showed a higher likelihood of biological vaccine escape than Delta because of mutations in its receptor-binding domain [48–50]. Correspondingly, hierarchical logistic growth models showed that the Omicron variant replaced Delta earlier and faster among individuals who had received two or more doses of the vaccine than among those who had not been vaccinated [46]. Nevertheless, attributing variant displacement solely to the vaccination requires a more comprehensive investigation and analysis. The complex interplay among various factors, including viral evolution, natural selection pressures, and community transmission dynamics, contributes to the emergence and dominance of specific variants.

1.6. Other pathogens

In addition to the aforementioned microorganisms, vaccine-induced strain replacement has been reported in other infectious agents, such as several strains of Mycobacterium tuberculosis [51], Neisseria meningitidis [52,53] and rotavirus [54–57]. A compartmental mathematical model of tuberculosis predicted that the advantages of vaccination would diminish if the selective elimination of one strain enabled a previously less competitive nonvaccine strain to resurface [51]. Additionally, a population-based surveillance study of invasive meningococcal disease suggested that the current predominance of serogroup B infections in Austria may be attributed to meningococcal vaccination campaigns targeting only serogroup C [58]. Furthermore, studies have demonstrated similar serogroup changes and vaccine-induced capsular switching in Neisseria meningitidis in other countries, including Canada, the Czech Republic and Spain [53]. Similarly, studies focusing on changes in rotavirus strain diversity before and after the introduction of the rotavirus vaccine have illustrated changes in the local distribution of rotavirus strains in Italy and Zambia, possibly attributable to vaccination [56,57].

Such instances underscore the complexity of the vaccine-mediated selection pressures and the subsequent ecological dynamics among pathogen populations, emphasizing the necessity for continual surveillance and adaptation of vaccine strategies to mitigate the risk of strain replacement.

2. Potential mechanisms involved in vaccine-induced pathogen strain replacement

Biologically, strain replacement occurs when a new strain shows increased absolute fitness within a population, or when the initial fitness of a strain decreases [59]. The absolute fitness of a pathogenic strain in a population is controlled by two quantitative assessments: the basic reproduction number and the invasion reproduction number. Basic reproduction number anticipates the number of secondary infections generated by a single infectious agent within a completely susceptible population [5]. While the reproduction number illustrates the initial pathogen dynamics within a wholly susceptible host population, the strain dominance within the host population does not solely rely on its capacity to invade such a population; rather, it also hinges on its ability to infiltrate an established population of another strain, as depicted by its invasion reproduction number. Accordingly, recent studies have proposed three main mechanisms underlying vaccine-induced pathogen strain replacement (Figure 1): differential effectiveness of the vaccine, differential ability to super- and co-infection and vaccine-induced metabolic shift, as follows:

Figure 1.

Potential mechanisms of vaccine-induced strain replacement.(A) In cases without a vaccine, the dominant strain outcompetes other strains and infects the majority of the population. The differential effectiveness of a vaccine creates opportunities for nontargeted strains to proliferate. Vaccines affect both the basic and invasion reproduction numbers of the targeted strain, leading to a decrease in its competitiveness within the population. As the infection rate of the dominant strain decreases, resources are made available for other strains in terms of susceptible hosts. (B) Elevated vaccination rates diminish the susceptible hosts for both strain A and strain B and decrease their infection rate when the pathogens exist independently. In the presence of a perfect vaccine that can target both strain A and strain B, the infection rate will drop for both strains. However, in the scenario where strain A can infect individuals who are already infected with strain B (co-infection or super-infection), strain replacement may occur. With the increase in vaccination rates initially, the vaccine supports the coexistence of both strains. With higher vaccination levels, strain A is eventually eliminated, and strain B becomes dominant. (C) There are three levels of bacteria categorization based on their polysaccharide capsule (serotyping), metabolic profile including substrate transporters (metabolic typing), and genomic sequence (genetic sequence typing). Under the selective pressure of vaccination, bacteria are found to initiate genetic recombination to transfer virulence-related factors. Genetic recombination may occur via either conjugation or transformation between vaccine-targeted and untargeted strains.

2.1. Differential effectiveness of the vaccine

Generally, applying a vaccine that is more effective against certain strains creates opportunities for other strains to thrive. When the dominant vaccine-targeted strain is diminished due to the effectiveness of the vaccine, it essentially opens up ‘resources’ in the form of susceptible hosts for the untargeted strains. The number of susceptible hosts for each strain affects the competitive dynamics between the different strains. In addition, herd immunity against vaccine-targeted strains further reduces the competition between strains for susceptible individuals [5]. Ultimately, a differentially effective vaccine decreases both the basic and invasion reproduction numbers of the target strain. This shift in competitiveness changes the absolute fitness of the targeted strain, leading to changes in its relative and overall presence within the population.

2.2. Differential ability of super- & co-infection

Mathematical models have demonstrated that even if the vaccine is equally or perfectly effective against all strains, pathogen strain replacement can still occur. Vaccination always decreases reproduction numbers, whereas invasion reproduction numbers depend on the vaccination rate, biological characteristics of the strains, and their interdependence in the absence of vaccination [5]. Strain replacement occurs when vaccination has opposing effects on the invasive abilities of the two strains. The differential ability to super- and co-infect strains creates an asymmetrical effect of the vaccine on the potential for invasion by the two strains. Iannelli and colleagues presented a theoretical example regarding this mechanism arising from an assumption where ‘strain 1’ can super-infect individuals already infected with ‘strain 2’ at the same time the reverse is infrequent [60]. In the presence of a vaccine affecting both strains 1 and 2, elevated vaccination rates lower the steady-state presence of each pathogen when they exist independently. However, when strain 2 is established, vaccination diminishes the resources available to strain 1, thereby reducing its ability to invade. Conversely, in scenarios where strain 1 prevails, decreasing its prevalence reduces superinfection rates, thereby enhancing the invasion potential of strain 2. A decrease in the invasion capability of strain 1 and a simultaneous increase in the invasion capability of strain 2 led to pathogen strain replacement.

2.3. Vaccine-induced metabolic shift

Several studies have shown that vaccination triggers genetic alterations in nonvaccine strains, potentially resulting in increased transmission and virulence. Watkins et al. used a mathematical model depicting genomic evolution in Streptococcus pneumoniae to show that viral components associated with vaccine serotypes transitioned to become linked with nonvaccine serotypes after vaccination [61]. The mathematical model uses genetic sequence types and metabolic types, in addition to serotypes, to further classify S. pneumoniae, each reflecting a different aspect of bacterial biology. Genetic sequence types provide insights into the genetic diversity of pneumococcal strains, helping researchers understand the evolutionary relationships and the transmission dynamics within populations. Pneumococcal strains are categorized into metabolic types (MT) based on their metabolic profiles, which include differences in transporters, substrate repertoires and substrate fermentation capabilities. These metabolic differences influence the bacterial ability to acquire nutrients and therefore thrive in the host environment. MTs reflect the functional aspects of pneumococcal biology and can affect strain fitness, transmission efficiency and pathogenicity. Introduction of vaccines targeting specific serotypes has been shown to exert a selective pressure on pneumococcal populations, leading to the transfer of vaccine-targeted metabolic and virulence-related elements to nonvaccine serotypes through recombination. In the same study, the authors suggested that capsular switch variants may exist before vaccination at low frequencies, but their expansion occurs only afterward because of decreased competition from vaccine strains. As a result, uncommon genetic variations might increase in prevalence owing to reduced competition with vaccine serotypes that have closely matched metabolic profiles. This shift in the metabolic traits among nonvaccine serotypes may alter the virulence and antibiotic resistance profiles of pneumococcal strains, leading to strain replacement at the population level.

3. Implications of the vaccine-induced pathogen replacement phenomenon

The vaccine-induced pathogen strain replacement phenomenon challenges the dynamics of disease control strategies, emphasizing the importance of continuous surveillance and adaptation in vaccine strategies. For example, the exploitation of vaccine-induced strain replacement to limit the prevalence and control the emergence of multidrug-resistant pathogens was suggested in a mathematical modeling study [62]. This study focuses on methicillin-resistant Staphylococcus aureus (MRSA) as a case study, illustrating the feasibility of targeting the multidrug-resistant genotype of S. aureus using a hypothetical vaccine combined with drug treatment while concurrently treating susceptible serotypes. This combined approach aimed to trigger a vaccine-induced shift in selection pressure, favoring less drug-resistant genotypes. This article highlights the potential of vaccine-based resistance control strategies to drive the evolution of drug-resistant pathogenic populations toward drug sensitivity. Furthermore, this mathematical model suggests that such combined intervention strategies can effectively limit the nosocomial outbreaks of drug-resistant strains, even with imperfect vaccine efficacy. Similar novel strategies could be used to capitalize on the inherent mechanisms of strain replacement to mitigate the spread and impact of multidrug-resistant strains.

4. Conclusion

Overall, understanding and leveraging vaccine-induced pathogen strain replacement significantly influences health policies, shapes vaccine strategies and provides innovative avenues for combating multidrug-resistant pathogens. Moreover, in the context of emerging and re-emerging diseases, such as influenza or pneumococcal infections, recognizing strain replacement informs the development of adaptable vaccines to better tackle evolving pathogen landscapes. This approach reflects the dynamic nature of pathogen evolution and underscores the necessity for adaptive and multifaceted interventions in the ever-evolving landscape of infectious diseases.

5. Future perspective

Vaccine-induced pathogen strain replacement is an obstacle that should be addressed in light of the worldwide mass vaccinations. While vaccines contribute to a decrease in morbidity and mortality related to various infectious agents, the phenomenon of concern has been shown to affect vaccine efficacy. If once was theoretical only, nowadays and in the near future vaccine-induced pathogen strain replacement is a real threat for vaccination. The latter was recently witnessed during the COVID-19 pandemic, where pressure over the virus contributed to the emergence of a new variant questioning, in a continuous fashion, the efficacy of the circulated vaccines. This behavior shown by the strains, which is directly related to vaccination and its targeted strains, will be encountered in the near future. In our opinion, the best approach is a thorough and detailed follow-up of the epidemiology of vaccine-targeted and untargeted strains, their distribution, clinical implications, and, most importantly, the morbidity and mortality associated with the concerned infections. Based on this, if feasible, vaccine components should be modified accordingly, and precautions, early detection, diagnosis, treatment and prevention of complications should be the main focus.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.