A Review of Comparative Strategies Against Pneumonia: Vaccine and Antibiotic Resistance Mitigation

3.1. Vaccine Efficacy

Multiple studies have measured the effectiveness of pneumococcal vaccines. For instance, the 13-valent pneumococcal conjugate vaccine (PCV13) has shown some impact. A study found that PCV13 had an adjusted vaccine effectiveness of 10.0% against pneumonia in adults [28]. A meta-analysis reported that PCV13 vaccination reduced the occurrence of vaccine-type invasive pneumococcal disease (IPD) in adults aged more than or equal to 65 years by 61.5% [29].

The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has also been examined, with more diverse results. A meta-analysis stated a pooled vaccine efficacy of 63% against IPD due to any serotype [30], while another study showed less effectiveness of 2% against PPSV23-type pneumococcal pneumonia in adults aged ≥65 years [31].

3.2. Antibiotic Resistance in Streptococcus Pneumoniae

Antibiotic resistance in Streptococcus pneumoniae is a major global health threat. Surveillance data show a high occurrence of resistance to commonly prescribed antibiotics. In the United States, it is estimated that more than 2 in 5 S. pneumoniae infections are caused by a strain resistant to at least one antibiotic [32].

A study investigating trends in the United States found that roughly 39.9% of S. pneumoniae isolates were resistant to macrolides, such as erythromycin, and 39.6% were resistant to penicillin [33]. In certain regions, the incidence of penicillin resistance has been reported to be as high as 45% [34]. These high rates of resistance limit treatment choices and highlight the importance of vaccination as a key prevention approach.

4.1. Combining DNA Vaccines with Advanced Delivery Mechanisms

DNA vaccines involve introducing genetic material encoding antigens into the host, leading to antigen expression and eliciting an immune response [35]. They are known for their stability, ease of production, and rapid adaptability to emerging pathogens [36-38]. Nanoparticle carriers, such as lipid nanoparticles (LNPs) and polymer-based nanoparticles, play a crucial role in enhancing the delivery of DNA vaccines. These carriers protect DNA from enzymatic degradation in the extracellular environment, ensuring it reaches target cells intact. Once delivered, nanoparticles improve the uptake of DNA by antigen-presenting cells (APCs), leading to a robust immune response. Lipid nanoparticles, already proven successful in mRNA vaccines like the COVID-19 vaccines, are being actively explored for DNA vaccine applications due to their high efficiency and biocompatibility [39]. Electroporation is a delivery technique that uses brief electrical pulses to permeabilize cell membranes temporarily, facilitating the direct uptake of DNA into cells. This method significantly enhances the efficiency of DNA entry, resulting in increased antigen expression and a stronger immune response. Electroporation is particularly valuable for DNA vaccines as it bypasses many cellular barriers, ensuring effective transfection and immunogenicity [40]. Injectable hydrogel systems represent an innovative delivery platform for DNA vaccines. These hydrogels can encapsulate DNA, offering controlled and sustained release at the site of administration. This prolonged antigen exposure promotes a stronger and more durable immune response. Hydrogels are biocompatible and can be engineered to release DNA in response to specific environmental triggers, making them a versatile option for vaccine delivery [41].

4.2. Use of Adjuvants to Enhance Immunogenicity

Adjuvants are critical components in modern vaccines, designed to amplify and extend the immune response to an antigen. They work by activating innate immunity, enhancing antigen presentation, and stimulating the adaptive immune system, which collectively improve the magnitude and durability of the immune response. By modulating immune pathways, adjuvants allow vaccines to achieve stronger protection with smaller antigen doses, improving efficiency and cost-effectiveness [42]. Their role is particularly vital in DNA vaccines, where adjuvants can compensate for the comparatively low immunogenicity of DNA as a vaccine platform [43].

4.3. Types of Adjuvants in DNA Vaccines

Alum-based adjuvants are among the oldest and most widely used in vaccines, inducing a depot effect that slowly releases antigens and promotes the activation of antigen-presenting cells (APCs). This sustained antigen exposure enhances the overall immune response. While traditionally used in protein-based vaccines, alum-based adjuvants are now under investigation for use in DNA vaccines to improve their immunogenicity and facilitate robust antibody production [44].

TLR agonists mimic pathogen-associated molecular patterns (PAMPs) to stimulate innate immunity via toll-like receptors. CpG oligodeoxynucleotides (CpG ODNs), for example, target TLR9 to enhance the immunogenicity of DNA vaccines by activating dendritic cells and promoting T-helper cell responses. This approach has shown promise in preclinical studies, demonstrating significant enhancement of both humoral and cellular immunity [45].

MF59, a squalene-based oil-in-water emulsion, is a well-known adjuvant that facilitates antigen uptake by APCs, leading to a robust immune response. Its efficacy has been demonstrated in various vaccine platforms and is being explored for DNA vaccine applications. MF59 is particularly effective at inducing a balanced Th1 and Th2 immune response, critical for comprehensive immunity [46, 47].

Nanoparticles as adjuvant carriers offer dual functionality by protecting DNA and delivering adjuvant molecules to APCs simultaneously. This co-delivery mechanism ensures optimal activation of the immune system while enhancing the stability and bioavailability of DNA vaccines. Lipid nanoparticles, which played a key role in mRNA vaccine success, are now being adapted to DNA vaccines to improve their performance [48-50].

Cytokine adjuvants, such as interleukin-23 (IL-23) and granulocyte-macrophage colony-stimulating factor (GM-CSF), are co-delivered with DNA vaccines to modulate immune responses. These cytokines enhance the activation and proliferation of T cells, promoting a strong and sustained cellular immune response. This approach is particularly valuable in vaccines targeting intracellular pathogens and cancers, where T-cell-mediated immunity is crucial [51].

In the following Table 2, we can see different adjuvants and delivery methods used to increase the efficacy of DNA vaccines.

5.1. Synergistic Impact

Vaccines play a pivotal role in reducing the incidence of infections that would otherwise require antibiotic treatment. By preventing bacterial infections, vaccines decrease the overall demand for antibiotics, which in turn reduces the risk of misuse and overuse —key drivers of antibiotic resistance [60]. For example, the widespread use of vaccines targeting viral respiratory infections, such as influenza vaccines, indirectly reduces secondary bacterial infections like pneumonia, diminishing the need for antibiotics [61].

In contrast, vaccines against bacterial pathogens, such as Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae, directly prevent diseases that would necessitate antibiotic therapy [62]. By curbing infections at their source, vaccines reduce the opportunity for bacteria to be exposed to antibiotics and develop resistance. This is particularly significant in regions with high rates of antibiotic misuse, where vaccination programs can serve as a critical intervention to slow the spread of resistant strains [60]. The introduction of vaccines targeting multidrug-resistant organisms, such as typhoid conjugate vaccines, exemplifies how immunization can act as a strategic measure against the global threat of antibiotic resistance [63].

5.2. Selective Pressures and Adaptation

While vaccines are powerful tools for disease prevention, their use can exert selective pressures on pathogens, potentially leading to evolutionary adaptations. For example, pathogens may alter their surface proteins to evade vaccine-induced immunity, as seen with certain strains of pneumococcus following the introduction of pneumococcal conjugate vaccines [64]. Monitoring these changes is crucial to ensure vaccines remain effective over time and to guide the development of next-generation vaccines.

The design of vaccines must carefully consider their impact on pathogen populations [65]. Overuse or improper deployment of vaccines can disrupt microbial ecosystems, potentially leading to unintended consequences, such as serotype replacement [66]. Therefore, balancing the scope of vaccine protection with a minimal ecological footprint is a key consideration in vaccine development and implementation.

5.3. Case Studies

The introduction of pneumococcal conjugate vaccines, such as PCV13, has significantly decreased the incidence of invasive pneumococcal diseases, including pneumonia, meningitis, and bacteremia [67]. In addition to improving public health, these vaccines have contributed to a notable decline in antibiotic use, as fewer bacterial infections necessitate treatment. PCV13 has shown effectiveness in reducing the prevalence of antibiotic-resistant strains of pneumococcus, showcasing how vaccines can complement antibiotic stewardship efforts [68, 69]. Despite the successes, challenges remain in fully leveraging vaccines to combat antibiotic resistance. Variability in vaccine access and coverage, particularly in low-resource settings, limits their impact on a global scale [70].

6.1. mRNA Vaccines as a Promising Alternative, Especially for Pneumonia

The unparalleled success of mRNA vaccines in the past few years has reframed vaccine development. mRNA vaccines demonstrated “extraordinary performance” against COVID-19, with high efficacy and safety, encouraging researchers to expand this approach to many diseases. In comparison, DNA vaccines were largely overshadowed during the pandemic era [81]. The agility of mRNA technology – from rapid design to mass production – is a critical advantage when facing pneumonia-causing pathogens, which can emerge or mutate quickly. For instance, influenza viruses and coronaviruses can evolve new strains; an mRNA vaccine can be reprogrammed with a new sequence in a matter of weeks, whereas modifying traditional vaccine platforms can take months. This speed is pivotal for timely responses to outbreaks of respiratory infections [81, 82].

From an immunological perspective, mRNA vaccines also appear well-suited for combating pneumonia pathogens. They induce strong neutralizing antibody responses and robust T-cell responses, which are important for clearing respiratory infections. A notable benefit for respiratory viruses is that mRNA vaccines can be formulated as multivalent or combination vaccines. Since the manufacturing process is similar for any mRNA, it is feasible to combine multiple mRNAs in one formulation. This has opened the door to combination vaccines for respiratory infections – for example, clinical trials are underway for a combined mRNA vaccine targeting COVID-19, influenza, and RSV in a single shot. Such integrated approaches could be especially valuable for protecting vulnerable populations against the array of viruses that cause pneumonia [83, 84].

It is important to note that DNA vaccines are not being abandoned; they continue to be explored, and some experts argue that certain drawbacks of DNA vaccines (like delivery inefficiency) might be overcome with new techniques. Indeed, DNA vaccine research is ongoing for various infections. However, at present, the momentum is clearly behind mRNA platforms. The ability to avoid genomic integration risks while achieving equal or greater efficacy gives mRNA vaccines a distinct edge. A 2023 review succinctly stated that, compared to DNA vaccines, mRNA vaccines have a more favorable safety profile and allow “adjustable expression” of the antigen without lingering in the body. This makes them an attractive option for diseases like pneumonia, where safety is paramount (when vaccinating healthy populations) and where we may want immune responses that are strong but not chronically overstimulated [85, 86].

6.2. mRNA Vaccine Developments for Pneumonia-Causing Pathogens

Several mRNA vaccine candidates targeting pathogens that cause pneumonia are in development, with some already achieving clinical success. Respiratory Syncytial Virus (RSV) is a common cause of pneumonia in infants and older adults for which no vaccine existed until recently. An mRNA vaccine (Moderna’s mRNA-1345, brand name mRESVIA) encoding the RSV prefusion F protein was tested in a Phase 3 trial in older adults. It demonstrated 83.7% efficacy in preventing RSV-associated lower respiratory tract disease in adults over 60. In 2024–2025, this mRNA RSV vaccine gained regulatory approval for adults ≥60 and for high-risk adults aged 18–59, after showing robust protection with no significant safety concerns. This marks a major advance, as traditional vaccine approaches for RSV had failed for decades. The success of the RSV mRNA vaccine illustrates how mRNA technology can deliver effective vaccines against difficult respiratory viruses. Streptococcus pneumoniae (pneumococcus) is the leading cause of bacterial pneumonia and is responsible for hundreds of thousands of deaths annually [87]. Current pneumococcal vaccines are polysaccharide–protein conjugates covering multiple serotypes, but researchers are exploring mRNA approaches to target pneumococcal proteins common to all strains [88].

As of 2025, no pneumococcal mRNA vaccine has entered clinical trials, but the concept is actively being investigated. Experts note that the mRNA platform proven in COVID-19 could be “readily adapted” to pneumococcal antigens. Preclinical studies are likely underway to assess mRNA vaccines encoding conserved pneumococcal proteins (such as pneumolysin or PspA) in animal models. One challenge in pneumococcal pneumonia is that the bacteria often colonize the upper respiratory tract; thus, an effective vaccine may need to induce strong mucosal immunity (e.g., secretory IgA and tissue-resident T cells) to prevent colonization and infection [89]. Researchers are examining whether mRNA vaccines delivered intramuscularly can be optimized (or perhaps given via intranasal routes in the future) to generate mucosal protection as well [90]. If successful, an mRNA pneumococcal vaccine could provide serotype-independent protection by encoding conserved antigens, potentially overcoming the serotype replacement issues seen with current conjugate vaccines. Beyond RSV and pneumococcus, mRNA vaccine research extends to other pneumonia-related pathogens. Influenza, a major viral cause of pneumonia, is the target of several mRNA vaccine programs aiming to improve upon traditional flu shots; mRNA flu vaccines can be rapidly updated for new strains and have shown promising immunogenicity in early trials [91, 92]. Another important pathogen is Mycobacterium tuberculosis, the bacterium causing tuberculosis (TB), which often manifests as a chronic form of pneumonia. TB is the leading cause of infectious disease mortality globally (approximately 1.3 million deaths per year) [93]. Bacillus Calmette–Guérin (BCG) vaccine provides inconsistent protection in adults. Recent preclinical studies have shown that an mRNA vaccine against TB can elicit strong T-cell responses and enhance protection in animal models [94, 95]. In a 2025 mouse study, a lipid-nanoparticle mRNA vaccine induced immunity that significantly reduced TB bacterial load in the lungs, and it served as an effective booster after BCG vaccination. Researchers noted that this mRNA approach could be a “game-changer for bacterial diseases like TB,” given its rapid adaptability and potent immunogenicity. These findings are paving the way for future clinical trials in humans. The adaptability of mRNA technology also allows for combination vaccines [96]. Companies are testing combined respiratory vaccines (e.g., a single mRNA-based shot for COVID-19, influenza, and RSV) to simplify protection against multiple pneumonia-causing viruses.

Such innovations could significantly reduce the pneumonia burden, especially in older adults who are at risk from various pathogens [97].

7.1. Use of Vaccines and Effective Delivery Systems

Vaccines play a pivotal role by preventing infections, thereby reducing the need for antibiotics and minimizing the emergence of resistant strains [98]. The World Health Organization (WHO) reports that vaccines against 23 pathogens could decrease global antibiotic use by 22%, equating to 2.5 billion defined daily doses annually [99]. Increasing funding and collaboration for vaccine research, particularly in relation to pneumonia, has now become an urgent area for global health consideration due to the persistent and deadly burden of this disease, particularly in children in developing regions. Pneumonia is responsible for the death of over two million children under the age of five every year worldwide; the great majority of these deaths occur in resource-poor countries, where therapeutic access remains low and vaccination coverage is inadequate [100]. The development and eventual delivery of effective vaccines, therefore, require not only scientific innovation but also strategic financial mechanisms and global partnerships to make it happen. One such strategy is the Advanced Market Commitment (AMC), which provides pharmaceutical companies with an incentive to pursue late-stage development by guaranteeing a market and subsidizing part of the cost of production for low-income countries. This innovative financial mechanism guarantees that manufacturers could sell the vaccines at an affordable price, bridging the commercial viability and public health need gap [101].

Public health interventions, such as improved sanitation, hygiene, and surveillance, complement vaccination efforts by controlling the spread of infections and ensuring the rational use of antibiotics. This integrated approach not only enhances disease prevention but also preserves the efficacy of existing antibiotics [102].

7.2. Rational Antibiotic Use

Encouraging rational antibiotic use alongside vaccine deployment is crucial to prevent the overuse and misuse of antibiotics, which are primary drivers of AMR. Implementing antimicrobial stewardship programs that promote appropriate prescribing practices, along with widespread vaccination, can substantially reduce unnecessary antibiotic consumption. The WHO underscores that vaccines can decrease the incidence of infections, thereby reducing the need for antibiotics and the subsequent development of resistance [103].

Despite these advances, however, challenges remain, such as the criticism of the AMC for being inflexible and detrimental to the adoption of other new, potentially better vaccines during its limited operational period. Besides, the risk of pneumonia is further aggravated by the presence of HIV, with children infected with HIV showing a 40 times higher propensity towards invasive pneumococcal diseases than uninfected peers. Clinical observations from South Africa and other excessively burdened areas indicated that more than 50% of children admitted due to pneumonia are HIV positive; this is a good reason to develop vaccines for immunocompromised populations [104]. Moreover, pneumonia pathogens, Streptococcus pneumoniae and Haemophilus influenzae type b, underscore the need for comprehensive vaccine coverage and multivalent formulations [105].

7.3. Global Efforts and Policy Recommendations: Strengthening Global Surveillance for Antibiotic Resistance

Antimicrobial resistance (AMR) poses a significant threat to global health, necessitating robust surveillance systems to monitor and combat resistant infections. The World Health Organization (WHO) has established the Global Antimicrobial Resistance and Use Surveillance System (GLASS) to provide standardized data on AMR patterns worldwide. This initiative aims to enhance the quality, quantity, and sharing of data on AMR, thereby informing national and international policies and strategies [106].

7.4. Policy Recommendations

To enhance global surveillance and scale down the impact of AMR in pneumonia, the following policy measures are recommended:

7.5. Increasing Funding and Collaboration for Vaccine Research

Advancing vaccine research is crucial for preventing infectious diseases and preparing for future pandemics. Collaborative efforts among governments, international organizations, and private entities are crucial to accelerate vaccine development and distribution. For instance, the Sabin Vaccine Institute emphasizes the importance of social and behavioral research grants to support immunization policies and programs, highlighting the need for increased funding and collaboration in vaccine research [114]. The AMC program for pneumococcal vaccines, primarily financed by major patrons, such as Canada, Italy, Norway, the Russian Federation, the United Kingdom, and the Bill & Melinda Gates Foundation, has committed $1.5 billion to secure vaccine availability and affordability to prevent five million deaths by 2030. Strong delivery systems, coupled with diagnostics and healthcare capabilities, are essential components in vaccination programs, especially for higher-risk immunocompromised infants. This is where the public-private partnership of the GAVI Alliance becomes crucial in reaching the neglected populations and sustaining immunization programs. Funding, innovating, and having readiness for flexible approaches will work in favor of further reduction of child mortality from pneumonia [104].

8.1. DNA Vaccine-Specific Challenges

The main problem with DNA vaccines has been their weak ability to provoke strong immune responses in human trials compared to animal models. This often necessitates high doses or repeated administrations, which is impractical for large-scale vaccination campaigns [73]. There is also a theoretical (but very low) risk that plasmid DNA could integrate into the host genome and alter host DNA, raising concerns about insertional mutagenesis or autoimmunity [115].

The need for the DNA plasmid to cross both the cell and nuclear membranes creates a delivery barrier, limiting transfection efficiency and antigen expression.

Most DNA vaccine plasmids contain antibiotic resistance genes as selectable markers during the manufacturing process. There is a theoretical concern about the horizontal transfer of these genes to gut microbiota or environmental bacteria, potentially contributing to antimicrobial resistance (AMR) [116].

In some cases, the prolonged, low-level antigen expression from DNA vaccines has been associated with the induction of immune tolerance rather than protective immunity, particularly for certain antigens [106].

8.2. mRNA Vaccine-Specific Challenges

mRNA vaccines, especially those using certain lipid nanoparticles (LNPs), can be associated with significant local and systemic reactogenicity, including fever, fatigue, and myalgia. While generally transient, this can impact vaccine acceptance and poses a challenge for use in vulnerable populations [39]. Despite improvements, mRNA is inherently less stable than DNA and typically requires storage at ultra-low temperatures (-20°C to -80°C) to maintain efficacy. This poses a major challenge for distribution in low-resource settings, where the burden of pneumonia is highest [84].

As a newer technology, long-term data on the durability of immune protection and the infrequent adverse events for mRNA vaccines are still being collected for various disease targets beyond COVID-19.

8.3. Platform-Agnostic Challenges

While promising, scaling up the manufacturing of complex formulations like LNPs for global supply remains a challenge [117]. The cost of goods for these novel vaccines is currently higher than for many traditional vaccines [118]. Public skepticism towards new genetic-based vaccine technologies remains a significant hurdle. Clear communication and transparency about the development, safety, and mechanisms of these vaccines are crucial for public acceptance. As with all vaccines, there is a constant evolutionary arms race. Therefore, continuous surveillance and platform agility are required to address this issue [119].