Vaccines and the Immune System: The Ultimate Protection

Introduction

Vaccines, altered forms of pathogens, enhance immunity by priming a host’s immune system, building up memory to improve the “secondary response” (1). The immune system is a network of pathways that protects the body through the innate and the adaptive immune systems (1). While the innate immune system acts as a general “first response” to foreign molecules, the adaptive system is a specific secondary response that develops after exposure to an antigen (1). Researchers focus on improving this secondary response by developing vaccines.

Background

Edward Jenner was one of the first to venture into the field of vaccine development.  In 1798, Jenner discovered that inoculations with cowpox, a weaker form of smallpox, helped build resistance to smallpox better than employment of the deadly pathogen itself (2). Almost a century later, Louis Pasteur observed that inoculating chickens with a weakened culture of bacteria built resistance to the disease (2, 3). Since these two discoveries, huge advances have been made in vaccine development.

Scientists now understand the science behind immunity. T cells, responsible for cell-mediated immunity, recognize and bind to antigens that are attached to pathogens (1). They reproduce and develop into T helper cells and cytotoxic T cells, which recruit other cells and kill antigen-presenting cells respectively (1). Unlike T cells, B cells recognize and bind to free antigens (4). They differentiate into plasma cells, which secrete large numbers of specific antibodies for a short period of time, and memory B cells, which stay in the body for a long time (4). Both B cells and T cells differentiate into cells with a memory for a specific antigen, making the secondary response faster and stronger (1).

With the knowledge provided by Jenner, Pasteur, and numerous other scientists, it is now understood that vaccines work through active immunization by stimulating the host to create T cells and B cells specific to the injected pathogen (1). When the body encounters these pathogens again, it can fight them much more effectively. This understanding enables the development of safer, stronger vaccines.

Types of Vaccines

There are many types of vaccines that can successfully prime the immune system, arming the host with an array of memory B and T cells that quickly mount a response and protect the host from infectious diseases.

Live Vaccines

The vaccines created by Jenner and Pasteur were both live and weakened versions of the pathogen, meaning that they still had the ability to reproduce within the host (2). Because live vaccines stay in the host’s system longer and more closely resemble the natural virus, they build the strongest immune response (1).

Scientists create attenuated vaccines by weakening pathogens with chemicals and using related animal viruses of weaker pathogenicity in humans (3). Growing the pathogen in conditions unlike those in the body to develop strains that will not be strong enough to cause disease is another common technique (3).

While live, weakened vaccines have their advantages, in some cases they can cause the inoculated individual to develop the disease or can transform into a more dangerous form of the disease (1). This change can occur through mutations in the virus that revert it to its pathogenic state or through recombination with other viruses present in the patient followed by further replication (5). In addition, other viruses can be introduced into the vaccine in the process of weakening the virus; these viruses can infect the patient when the patient is injected with the weakened virus (5). During their production in cell culture or as a result of the attenuation process, some of the first live polio vaccines were contaminated by SV40, a virus found in monkeys that does not harm humans (5). Doctors in the United States have not used the live oral poliovirus vaccine since 2000 due to the risk of permanent paralysis associated with the reversion of the live vaccine to its pathogenic state (6). Each year in the United States, there were six to eight cases of vaccine-associated paralytic polio, and, after successful eradication of the disease resulting from vaccination programs, this risk was higher than the risk of acquiring the disease from the wild-type pathogen (6).

Through improvements in genetic engineering, vaccines containing a combination of live, attenuated virus and protective agents have been created, making these vaccines much safer (3). Researchers have also discovered genes necessary for replication of viruses; by deleting these genes, researchers can prevent replication in the host while allowing for expression of genes in the pathogen that provoke an immune response (7). Scientists are also looking into the use of RNA interference, such as microRNAs, which can block translation of specific RNA sequences to protein (7). By including more microRNA binding sites in vaccines, the engineered virus can be further attenuated (7).

The methods discussed above are still being investigated. Nevertheless, current live vaccines are able to provide sufficient protection. For example, without the live, attenuated measles vaccine, there would be an estimated 2.7 million deaths around the world due to the disease (8).

Inactivated Vaccines

Scientists create inactivated vaccines by “killing” the pathogen with heat or by chemical means (1). By disabling the pathogen in these ways, scientists can prevent replication within the host but still prompt a protective immune response (1). Inactivated vaccines are considered safer than live, attenuated vaccines because they cannot replicate in the host and thus have a lesser chance of causing disease (1). In addition, in the process of killing the target pathogen, all other viruses and pathogens are killed, eliminating another problem associated with the attenuation process (5).

On the other hand, inactivated vaccines require more than one vaccination because of the lower level of exposure to the pathogen. With inactivated vaccines, there is a shorter exposure period because of a lack of replication and the more altered form of the virus (1).

Perhaps one of the most famous inactivated vaccines is the polio vaccine created by Jonas Salk in 1952 (9). Salk created his polio vaccine by inactivating three different strains of the poliovirus (9). Improvements in cell culture and preservation allowed scientists to grow kidney cells from monkeys and infect these cells with a virus (9). After letting the virus replicate and allowing the cells to respond, the infected cells were filtered and inactivated with formaldehyde to kill the polio virus (9). According to the Center for Disease Control, before the inactivated polio vaccine there were “13,000 to 20,000 cases of paralytic polio […] each year in the United States,” but the disease has now been effectively eradicated in the U.S. (8).

Inactivated vaccines targeting HIV are now under development. A research team in Canada has created a whole-killed HIV-1 vaccine, which has a version of the virus that was engineered and then inactivated by researchers (10). Because scientists engineer and modify the disease to make the vaccine, it can be widely produced and is not pathogenic (10). During its Phase 1 clinical trials, this vaccine has been shown to increase the amount of antibody against viral coat proteins that allow HIV to attach to and invade cells, and against proteins that make up the viral core of HIV (10). If these vaccines are successful, they could help some of the 34 million people around the world living with HIV (10).

Subunit Vaccines

While the inactivated and activated vaccines discussed above include the entire pathogen, subunit vaccines only deliver the specific antigen or antigens that prompt the largest immune response (11).  Because subunit vaccines do not contain all of the elements of the pathogen, they are less likely to have negative side effects (11).

Subunit vaccines are being considered as a potential vehicle for cancer vaccination. Scientists target proteins that are altered or overexpressed in cancel cells (12).

For example, MUC1 is a protein found on the surface of most healthy cells, and it plays a role in various cell functions depending on the agent that binds it (12). However, in cancer patients, this protein is overexpressed, expressed in new locations, and demonstrates abnormal protein-to-protein binding, suggesting a structural change (12). Upon injection with tumor-antigen-associated MUC1, scientists saw increased antibody production, but it is too soon to say whether or not this vaccine is effective.

The only approved cancer vaccine is Provenge (13). Researchers create this vaccine by taking white blood cells from a patient and exposing them to a protein found in prostate cancer cells (13). Upon exposure to these proteins, these blood cells are then put back into the patient (13). This vaccine increases the life expectancy of patients, but does not cure the cancer (13).

While subunit vaccines have proven successful in some cases, they have many faults as well. Because subunit vaccines only contain certain components of entire pathogens, they must be introduced with an adjuvant, an agent that increases the effectiveness of vaccines by enhancing the immune response (7). Adjuvants can elicit antigen expression and direct antigens to locations that will produce the largest immune response (7). Because of complications like the need for adjuvants, some scientists believe that subunit vaccines are not comprehensive enough and are pushing for more investigation into the field of whole-cell vaccines, where killed tumor cells are injected into patients (12).

Recombinant Vector Vaccines

Recently, scientists started developing vaccines by inserting portions of DNA from pathogens into innocuous viruses and injecting these recombinant vectors into patients (11). The weakened or harmless virus can reproduce in the host, simultaneously producing the inserted pathogen’s antigens (1). There is still much testing that must be done before recombinant vector vaccines can be used widely, but improvements are happening quickly.

Like those who are working on inactivated vaccines, scientists in the field of recombinant vector vaccines are looking into creating a vaccine for human immunodeficiency virus (HIV), but are following a different path. Currently, researchers find it difficult to cover the variability of HIV between and even within patients due to its fast replication and mutation in a host (14). There are also many different families of HIV, making it difficult to decide which proteins and other factors should be encoded in the virus to prime the immune system (14).

Researchers now believe that employing a mixture of adenoviruses – common human viruses that can efficiently invade human cells – may be the answer (14). By keeping particular promoters and coding sequences in the DNA insertion in the adenovirus and having a mixture of these viruses, scientists can cover a wide variety of HIV (14).

In addition to concerns regarding variability of diseases themselves, scientists worry about pre-existing immunity to the viral surrogate used to bear DNA insertions (14). In terms of recombinant vectors, adenoviruses are fairly common, and some people may have gained immunity to adenoviruses through exposure in everyday life (14). Many have tried to choose vectors from less common viruses, but find trouble with certain gene interactions that prevent the new vector virus from successfully producing the desired antigen (14). By replacing certain coding regions, scientists have overcome these boundaries (14).

In one vaccine now in clinical trial in Africa, scientists have inserted part of the HIV virus into a weakened form of the Sendai virus, a virus that causes influenza in rats and is even less harmful to humans (15). The Sendai virus is a viable alternative to adenoviruses; it is less commonly encountered by humans in everyday life, meaning fewer populations are immune to it. After injection with the vaccine, the virus can reproduce within the host and create proteins characteristic of HIV, causing an immune response (15).

Conclusion

Researchers have made huge discoveries since Edward Jenner developed the first vaccine at the end of the 18th century (2). While the immune system can effectively protect individuals in a variety of cases, vaccines can increase this protection. These vaccines range from weakened, but complete versions of viruses to small subunits consisting of essential proteins, and each type has its own strengths and weaknesses. These vaccines have saved the lives of many in the past and, with continuing research, the development of new or improved vaccines will save even more lives in the future.

Contact Stephanie Alden at

stephanie.l.alden.16@dartmouth.edu

References

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4. P. Fisher, Immunology Module (2008). Available at http://missinglink.ucsf.edu/lm/immunology_module/prologue/objectives/obj05.html

5. J. Victoria et al, Viral Nucleic Acids in Live and Attenuated Vaccine: Detection of Minority Variants and an Adventitious Virus. J Virol. 84. 6033-6040 (April 2010). 

6. W. Egan, Testimony at Hearing: SV40 in Polio Vaccine, Washington, D.C., 13 November 2003.

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8. Centers for Disease Control and Prevention, What Would Happen If We Stopped Vaccinations? (June 2013). Available at http://www.cdc.gov/vaccines/vac-gen/whatifstop.htm#intro

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11. NIAID, NIH, U.S. Department of Health and Human Services, Understanding Vaccines: What They Are, How They Work (NIH, January 2008).

12. S. Boghossian, A. Von-Delwig, Tumor Vaccines, Monoclonals, Proteins, or Whole Cell Therapies. J Vaccines Vaccin. S1:003. 1-10 (2012).

13. American Cancer Society, Cancer Vaccines (February 2013). Available at http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/immunotherapy-cancer-vaccines

14.E. Emini, J. Shiver, Recent Advances in the Development of HIV-1 Vaccines Using Replication-Incompetent Adenovirus Vectors. Ann Rev Med. 55. 355-372 (February 2004). 

15. J. Gilmour, “New AIDS vaccine trial launched in UK, Africa.” Nightly News. By Victoria MacDonald. London, UK: NBC, 2013. Web.