The human immune system is the body’s most advanced weapon, capable of defending us against every possible foreign danger. From commonplace environmental irritants, such as pollen or smoke, to deadly viruses like HIV, our immune system utilizes the various weapons in its arsenal to respond. This process is a highly coordinated dance with complex interactions between various systems, of which vaccines affect and take part in. To understand the role of vaccines in immunity, it is first important to understand key functions of the immune system.

The overall immune response is divided into two major arms: innate and adaptive immunity. The various immune cells you may have heard about can be categorized by which effective phase of immunity they carry out. Cells like neutrophils and macrophages are part of innate immunity, and they are the “first responders” who are immediately on the scene of injury or infection. Cells such as T-lymphocytes and B-lymphocytes are part of adaptive immunity, and they respond in a delayed manner following the innate immune cells [1]. Though slower in nature, this response is extremely powerful. The adaptive immune system is also very aptly named. Through our natural encounters with various pathogens, or disease-causing organisms, specific T-cells and B-cells and their own respective cellular products are generated. This function is exclusive to the adaptive immune system, allowing it to mount a targeted response against a current pathogen, as well as retaining immune memory of the infection, granting long-term immunity against a pathogen if encountered again [3]. Essentially, you can think of the adaptive immune system like a library or headquarters: information on threats is received, stored, and appropriate responses are planned and executed. This function of both memory and constant adaptation is what allows our immune system to build a natural and robust response to unknown dangers across our lifetime [1] (Chapter 1 How the immune system works).

Vaccines are man-made attempts at boosting our adaptive immune system. As described previously, active immunity is usually gained through natural encounters with and fighting off foreign pathogens [2] (CDC active vs passive immunity). Largely, most people with healthy immune systems are able to recover from random encounters with diseases, building up lifelong active immunity against multiple pathogens along the way. The function of vaccines is to intervene and boost active immunity against pre-selected pathogens, which are deemed too dangerous to risk natural infection [3] (CDC Chapter 1). Thus, the goal of vaccines is to arm our adaptive immune system with specific weapons beforehand, so that when we do eventually encounter a dangerous pathogen, we can be more confident in our body’s efforts to counter it and avoid associated harmful effects.

How do we design vaccines to prime the immune system without causing an actual infectious response? Here, vaccine design can be described in two major branches: live versus non-live vaccines. The key difference between these two forms is whether the vaccine agent is able to replicate on its own or not.

Live vaccines, as named, are essentially “alive,” and once injected, replicate within the body like a real virus or bacteria to stimulate an immune response akin to the process of a natural infection [3] (CDC Chapter 1). This sounds scary, as we are essentially allowing bacteria and viruses to directly infect us. However, this mechanism belies the main purpose of live vaccines: to mimic a natural infection as closely as possible in order to generate the most effective immune response in preparation against encountering the actual pathogen [3]. Furthermore, the man-made designs of live vaccines ensures that the benefits of vaccination greatly outweigh the risk of a vaccine-induced infection. This is achieved in three possible methods:

The first type of live vaccine is derived from a pathogen closely related to the original, but which does not cause the same lethal disease. This is the design behind the Bacillus Calmette-Guéri (BCG) vaccine, which is generally used outside of the US in countries with a high burden of tuberculosis to stimulate immunity through exposure to its weaker cousin Mycobacterium bovis [4](BCG source).  The goal of these vaccines is to avoid the consequences of serious infection and provide cross-protective immunity, where immunity against a similar pathogen will hopefully provide the same protection when encountering the actual pathogen.

The majority of live vaccines are attenuated pathogens, meaning they are weakened versions of the original. This effect is achieved in two different ways: by culturing multiple generations of a pathogen until they lose the ability to harm but retain the ability to replicate or by using genetic engineering tools to change the harmful genes in the pathogen [5] (Sigma aldritch). Some live attenuated vaccines include the measles, mumps, rubella (MMR) vaccine, the intranasal influenza vaccine, or the oral poliovirus vaccine [6] (HHS).

A third form of live vaccine is the reassortant vaccine virus, which acts like a sheep in wolf’s clothing. It is similar to the other two types of live vaccines in that it also involves a weaker live pathogen as the main agent. However, it is reassortant, which means that it is combined with the genetic material of another pathogen to make a “vaccine virus.” After the vaccine virus enters our cells, its combined genetic material is used as an instruction manual to make proteins. These proteins, which are sensed as foreign material, exposes our immune system to components of the original, intended pathogen. This design thus encourages the development of protective immunity against the original pathogen without any risk of causing the actual disease [7] (Recombinant vaccines). This is the design behind the Ebolavirus vaccine virus, which uses the less harmful vesicular stomatitis virus to carry a small portion of the Ebolavirus to stimulate immunity [8] (CDC Ebolavirus vaccine).

This table summarizes the major forms of live vaccines:

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Contrast live vaccines against non-live vaccines, which are not able to replicate on their own when injected in the body. Non-live vaccines rely on repeated exposure to the immune system and don’t establish long-lasting immunity, which is why these vaccines often require repeated injections over various time courses to boost immune responses. In contrast, live vaccines usually use an initial series of injections to establish life-long immunity [3] (Ch 1 CDC). Non-live vaccines also come in three major designs:

One form of non-live vaccines is an inactivated whole-cell pathogen. Injecting this inactivated version imitates the live vaccine with the goal of exposing the immune system to the entire pathogen and all of its naturally occurring immune stimulating components. In this case, because the pathogen is inactivated, it loses its ability to replicate and any ability to cause the actual disease [3]. However, the inactivating process may also reduce the immunogenicity, or the ability to stimulate a protective immune response, of the vaccine, leading to a less robust immune response. An example of an inactivated vaccine is the polio virus vaccine, which has replaced the live oral polio virus vaccine due to its decreased risk of causing active infection [6, 9] (HHS, ch.4 cdc).

The most common non-live vaccines are subunit vaccines, which are generated by identifying specific components of the pathogen and modifying them into a vaccine to elicit a targeted immune response [3, 7]. These subunits can vary greatly across different pathogens and require an understanding of and ability to identify which portions of the pathogen are most immunogenic. Common subunit vaccines include the pneumococcal vaccine, the intramuscular influenza vaccine, and the tetanus diphtheria acellular pertussis (Tdap) vaccines [6] (HHS).

Of notable importance is the nucleic acid vaccine, with the most prototypical example being the mRNA COVID-19 vaccine. mRNA is made of nucleic acids, the same genetic material as DNA, and it serves as instructions for our cells to make whatever is encoded. In this example, the COVID-19 mRNA vaccine encodes information on how to produce the spike protein, which is the subunit portion of the virus we want our immune system to generate a response against. Once these subunits are produced by natural cellular machinery, it is transported outside the cell and identified by our immune system as a foreign substance [6] (HHS). Compared to the subunit vaccines, which must be appropriately dosed and injected, the benefit of the mRNA vaccine comes from the use of our own cellular machinery to provide the immune stimulation, allowing for maximized exposure to the pathogen subunit before the mRNA naturally degrades.

This table summarizes the major forms of non-live vaccines:

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Between live and non-live vaccines, there are a few key differences which can indicate individual responses and benefits to using either. Since live vaccines most accurately mimic the natural infection, they also elicit a similarly strong immune response [3]. Remember, the majority of our immune defense is generated naturally through random encounters with various pathogens and provides lifelong immunity. Thus, the mimicry of live vaccines usually provides a stronger, broader, and long-lasting response to a pathogen.

In contrast, the use of non-live vaccines, especially specific target subunit vaccines, only elicit a specific response limited by the injected amount. This is why subunit vaccines for pathogens that mutate often such as the influenza virus need to be modified yearly to try and capture the most relevant subunits for immunity. Additionally, multiple doses are needed to consistently maintain immunity, which can be seen with the Covid-19 booster shots or the Tdap booster every 10 years.

A simple way to visualize this difference would be to compare your immune system to a student studying for a test and live and non-live vaccines as different study materials [3]. The student will perform better on the real test day (e.g. when the immune system encounters the real pathogen) if previously given a set of practice problems that mimic the real test as closely possible (e.g. live vaccine), such as in the variety and the difficulty of the problems (e.g. live vaccines preserve all the different components of the whole pathogen). Afterwards, because they learned the material thoroughly the first time, they are more likely to remember the knowledge and be able to pass if tested again (eg. lifelong immunity with an initial series of shots). However, a student who is given a specific set of problems that only address one aspect of the test (eg. non-live subunit vaccine) is probably able to perform well against that one aspect, but does less well on the overall test. In the future, if they take that test again, they will most likely not recall the knowledge as thoroughly and require review again to prepare for the test (eg. booster shots).

Live vaccines seem to have an overall advantage over non-live vaccines in the effectiveness and strength of immunity conferred. However, the major concern would be the dreaded side effects. Because live vaccines are able to replicate and function like natural viruses, there is the possibility for them to cause actual disease. It is important to underscore the fact that live vaccines are weakened to the extent that they do not usually cause the same severe disease of the original pathogen. Within the majority of healthy individuals receiving the live vaccine, their immune system is able to handle and clear the vaccine without any symptoms.

When there are symptoms following a vaccine, these are usually much milder and non-specific such as pain or swelling at the site, fever, headache, or fatigue [10] (vaccine possible side effects). These are notable adverse events and can occur by chance in association with any kind of vaccination. However, to establish a direct causal relationship between the contents of the vaccine itself and occurring symptoms, more stringent evidence and investigation is needed [9] (Ch.4 vaccine safety).

In summary, anyone receiving a vaccine can experience these non-specific symptoms, but these are usually not symptoms of disease caused by the vaccine itself. Thus, the fear we have against live vaccines causing actual infection truly only applies to small portions of the population who are immunocompromised, indicating that their immune system is weaker than the baseline healthy individuals’ and cannot effectively mount the same response against vaccines and pathogens.

Herd immunity, or the collective immunity of the general community due to their tolerance of live vaccines, is the major mechanism by which these patients are protected from infection  [11].  Immunocompromised members of our community, such as transplant patients, people with HIV, pregnant individuals, face the largest risk of developing severe infection from live vaccines. They benefit more exclusively from non-live vaccines and rely heavily on herd immunity for safeguarding against infections from pathogens countered by live vaccines [6,10]. The table below summarizes the major aspects of live versus non-live vaccines:

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Within vaccine design, live and non-live vaccines provide many different ways to prime our body with the necessary immunity to combat dangerous microbes. There are benefits and drawbacks to both types of vaccines and we must acknowledge no vaccine is without complete risk [9].

Since the mid-20th century, the public health initiative to implement routine childhood vaccinations has demonstrated its overwhelmingly positive impact on decreasing the fatalities and complications from preventable disease [11,12]. It is no small feat that major drivers of global infection such as smallpox and polio are no longer the death sentence they once were, with vaccines eradicating smallpox and polio on target to achieve the same fate [11]. There is no great exaggeration in stating the benefit vaccines have had on societal and global health, with the WHO estimating currently available vaccines preventing 4–5 million deaths worldwide annually and a 90-100% decrease in morbidity from vaccine-preventable diseases due to the effects of herd immunity [11, 13]. WHO poses a further estimate of 1.5 million deaths which are completely preventable if access to childhood vaccines is increased (WHO vaccines) [13].

As a medical product, vaccine safety should be considered carefully and communicated with transparency to the public. There is a range of possible adverse effects that can result from vaccine administration, and in cases of severe complications, the appropriate risk and safety level of the vaccine should be assessed with a strong body of evidence. However, there is a baseline high standard of safety required of vaccines due to their use with the general public. Vaccine monitoring is also ongoing, leading to appropriate changes in recommendations over time.

The dynamic nature of vaccine policy can be seen with the aforementioned use of the live oral poliovirus vaccine. The live oral vaccine was beneficial to prevent the spread of polio when it was more prevalent in the population. Now, as we  near the global eradication poliovirus, the circumstances surrounding polio have changed and the possible risk of reactivated disease from the live vaccine led to a reevaluation in the live oral vaccine’s risks vs. benefits within this new context This reevaluation has led to updates in the recommendation to the current use of the inactivated poliovirus vaccine instead [9] (Chapter 4 CDC Vaccine safety). Thus, the use of vaccines balances widespread protection with possible risks, in which the maintenance and improvement of their impact depends equally on our effort as a community to share scientific knowledge in a manner that is transparent, educational, and promotes public trust in vaccine usage.

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References

1. Sompayrac LM. How the immune system works. Lecture 1: An overview. In: How the Immune System Works. 7th ed. Chichester: John Wiley & Sons; 2022. p. 1-11. ISBN: 9781119890683.
2. Centers for Disease Control and Prevention. Types of immunity [Internet]. Atlanta (GA): CDC; [cited 2026 Jan 29]. Available from: https://www.cdc.gov/vaccines/basics/immunity-types.html
3. Centers for Disease Control and Prevention. Principles of vaccination. Epidemiology and prevention of vaccine-preventable diseases (The Pink Book) [Internet]. Atlanta (GA): CDC; [cited 2025 Jan 29]. Available from: https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-1-principles-of-vaccination.html
4. Plotkin S, Orenstein W, Offit P, Edwards KM. Plotkin’s vaccines [Internet]. 7th ed. Philadelphia: Elsevier; 2018 [cited 2026 Jan 29]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459455/
5. Merck KGaA (Sigma-Aldrich). Cell-based vaccine manufacturing process for attenuated viral vaccines [Internet]. Darmstadt (Germany): Merck KGaA; [cited 2026 Jan 29]. Available from: https://www.sigmaaldrich.com/US/en/technical-documents/technical-article/pharmaceutical-and-biopharmaceutical-manufacturing/vaccine-manufacturing/cell-based-vaccine-manufacturing-process-attenuated-viral-vaccines
6. U.S. Department of Health & Human Services. Types of vaccines [Internet]. Washington (DC): HHS; [cited 2026 Jan 29]. Available from: https://www.hhs.gov/immunization/basics/types/index.html
7. European Patients’ Academy on Therapeutic Innovation (EUPATI). Types of vaccines [Internet]. [place unknown]: EUPATI; [cited 2026 Jan 29]. Available from: https://toolbox.eupati.eu/resources/types-of-vaccines/
8. Centers for Disease Control and Prevention. Ebola vaccines for healthcare professionals [Internet]. Atlanta (GA): CDC; [cited 2026 Jan 29]. Available from: https://www.cdc.gov/ebola/hcp/vaccines/index.html
9. Centers for Disease Control and Prevention. Vaccine safety. Epidemiology and prevention of vaccine-preventable diseases (The Pink Book) [Internet]. Atlanta (GA): CDC; [cited 2025 Jan 29]. Available from: https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-4-vaccine-safety.html
10. Centers for Disease Control and Prevention. Possible side effects from vaccines [Internet]. Atlanta (GA): CDC; [cited 2026 Jan 29]. Available from: https://www.cdc.gov/vaccines/basics/possible-side-effects.html
11.  Kayser V, Ramzan I. Vaccines and vaccination: history and emerging issues. Hum Vaccin Immunother. 2021;17(12):5255–68. doi:10.1080/21645515.2021.1977057. PMID: 34582315; PMCID: PMC8903967.
12. World Health Organization. A brief history of vaccination [Internet]. Geneva: WHO; [cited 2026 Jan 29]. Available from: https://www.who.int/news-room/spotlight/history-of-vaccination/a-brief-history-of-vaccination
13. World Health Organization. Immunization: facts in pictures [Internet]. Geneva: WHO; [cited 2026 Jan 29]. Available from: https://www.who.int/news-room/facts-in-pictures/detail/immunization

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