Live recombinant vaccines are biological preparations that improve immunity through the use of live bacteria or viruses that are genetically modified. These live pathogens are biologically engineered to express exogenous antigens in the cytoplasm of target cells, triggering immune responses as a result.[1] This form of vaccine combines the beneficial features of attenuated and recombinant vaccines, providing the preparation with attenuated vaccines’ long-lasting immunity and recombinant vaccines’ genetically engineered precision and safety.[2]

Live recombinant vaccines can be administered in less invasive ways, compared to the traditional injection of vaccines, such as orally or nasally. Common examples of vaccines with the aforementioned route of admission include the oral polio vaccine and the nasal spray influenza vaccine.[3][4] These vaccines not only offer a more convenient method of administration but also yield additional advantages. For example they can stimulate mucosal immunity and the eliminate the adverse effects associated with injection, tbenefits that are not attainable with conventional vaccine approaches.[5] Presently, ongoing research and development efforts are focused on enhancing live recombinant vaccines to offer heightened protection and broader coverage against various bacteria and virus serotypes.[6]

About

History

Edward Jenner, an English Physician, who created the first ever vaccine.

In fighting off countless diseases and outbreaks, technology has been a catalyst for the production of various types of vaccines. The general ideology of vaccines is to expose the virus to the human body to instigate an immune response as a primary response. Having the primary immune response after contracting the virus will lead to a quicker immune response when exposed to the same virus the next time. Vaccines are a first-line method of prevention of a community contracting viral diseases and not a prevention of the virus/disease from spreading. The first vaccine created was for smallpox where Edward Jenner used cowpox as the substance that created immunity to smallpox in people who got their resistance tested.[7] Notable vaccines followed using different technologies in helping the world strike a response towards disease and viral outbreaks; they include polio, flu (influenza), hepatitis A and B, measles, rotavirus and pneumococcal disease.[8]

The variety of vaccine types may create ambiguity as to how they function and what measures to keep their sustainability and efficacy. Unlike other vaccine types, recombinant vaccines use double the technology to help build immunity in an organism. A handful of vaccine types use the inactivated form of the virus to generate an immune response from injection into the body such as toxoid and inactivated vaccines. The distinction between live and inactivated vaccines is, however, not the only factor that differs between them. The different types of live vaccines include live attenuated (MMR-II), mRNA (COVID-19), viral vector (Ebola), subunit vaccines (Hepatitis) and the focus of this article, live recombinant vaccines. Even though it may sound the same, the pivotal difference is those live recombinant vaccines contain the live forms of the genetically modified virus whereas recombinant vaccines like subunit vaccines only use a part of the pathogen, which is not live.[9]

Features / Mechanisms

T and B cell Activation

Like live attenuated vaccines, live recombinant vaccines function by simulating natural infection. This is done through the injection of live pathogens into the host, where they will then replicate in the body to stimulate various immune responses, including the activation of T- and B-cells for the eradication of infected cells and invading pathogens respectively.[10][11] With a mechanism similar to infections that occur naturally, live recombinant vaccines can generate immunity that is robust and long-lasting.[2] However, unlike weakened pathogens in live attenuated vaccines, which can cause disease in hosts with immune-compromised, damaged or weakened immune systems, the viruses or bacteria used in live recombinant vaccines are genetically engineered; examples include gene editing or recombinant DNA technology, to have their disease-causing ability inhibited.[12][13] This helps in reducing the chances of the aforementioned individuals from being infected after vaccination.

Vaccines

A few of the many live recombinant vaccines include:

Oral Polio Vaccine (OPV)

The Oral Polio Vaccine, also known as OPV, is a live-attenuated recombinant vaccine, invented by Albert Bruce Sabin, that is administered orally for the treatment and prevention of polio.[3] Sabin's invention has been approved by the World Health Organisation (WHO) in countries like Belgian Congo and Cuba before entering the United States as an approved and used oral vaccine.[14] Despite the US discontinuing OPV due to its lack of effect on children, it is still used in many African countries.[15] OPV provides protection to polioviruses in all three forms by triggering antibody production in blood to prevent polio paralysis and virus malignancy.[16] OPV has made a significant impact in the sense that it ceased transmission of polio in outbreaks unlike IPV (Inactivated Poliovirus Vaccine) which only immunised the vaccinated individual.

Rotavirus Vaccine

Rotarix, an FDA-approved rotavirus vaccine manufactured by GSK, comes in liquid form as a live-attenuated vaccine. This two-dose scheduled vaccine targets infants ages ranging from 6 to 24 weeks and is indicated to prevent rotavirus gastroenteritis through a remodified version of rotavirus that uncovers a specific protein in another strain of rotavirus.[17] As a recombinant live vaccine, the vaccinated babies will gain immunity from gastrointestinal problems like diarrhoea and vomiting. An equivalent and broader prevention of rotavirus types (including G1, 2, 3, 4, 9) is RotaTeq manufactured by Merck as a live, oral and pentavalent vaccine.[18][19] Despite needing a third dose for full effect, both vaccines are effective in preventing rotavirus in infants.

Zoster Vaccine

Another live recombinant vaccine by GSK is called Shingrix. The indication of Shingrix is for adults of ages 50 and older with shingles, otherwise known as herpes zoster.[20] Herpes zoster can be contracted from a virus called varicella-zoster (VZV); identically to the one that induces chickenpox.[21][22] On the same token, chickenpox and shingles are not mutually exclusive in that shingles may arise from the reactivation of the VZV after having chickenpox. Shingrix contains a weakened and genetically modified form of the varicella-zoster virus.[23] The risk of the virus reactivation creating symptoms like excruciating pain and blisters can be prevented and treated by the recombinant antiviral vaccine. It, however, does not prevent chickenpox. Although people cannot contract shingles from a shingle-positive person, it can spread to people who have yet to have chickenpox which can be hindered by Shingrix.[23][24]

Influenza Vaccine

A quadrivalent recombinant live vaccine FluMist, developed by AstraZeneca, aims to fight off and mainly prevent influenza type A and B by immunising people with this vaccine.[4] It is indicated for going against 4 subtypes of influenza viruses: H1N1 and H3N2 for type A influenza, and 2 influenza B types. Flumist is for healthy people aged 2 to 49 and it comes in a special application of a vaccine, a nasal spray vaccine, unlike other conventional injection methods.[4][25] As a recommended option by the Centre for Disease Control and Prevention (CDC), the technology in this nasal spray vaccine contains a genetically modified weakened version of the influenza to build immunity by expressing a particular protein in the body.

Clinical Use

Administration

Flumist, an intranasal vaccine.

Like many other vaccines, live recombinant vaccines can be administered intramuscularly or subcutaneously. But apart from the traditional injection methods, live recombinant vaccines can also be taken orally, e.g. oral polio vaccine (OPV), reducing the invasiveness of vaccine administration, eliminating the adverse effects associated with injection and also elicit mucosal immunities, all of which are not achievable with traditional injections.[6][5] Additionally, live recombinant vaccines can also be taken through the nasal membrane in the form of a nasal spray, e.g. FluMist. This method of administration, like oral administration, is non-invasive and can stimulate mucosal immunity as well.[26] These non-traditional vaccine administration methods do not require a high level of skill and can thus be performed by regular adults, which can aid the process of mass vaccination during the outbreak of infectious diseases.[26][27]

Research on Developing Vaccines

Pfizer's Prevnar 13

The suppression of infectious diseases from spreading is still a global challenge the medical world is trying to handle. Various technologies have been explored in developing different types of vaccines including a subgroup of recombinant vaccines using protein, viral vectors and conjugate to name a few.[28] Although the current vaccines available can treat fatal diseases like pneumococcal disease and HIV, there is much room for improvement and broadening of the treatment scope. Pfizer's Prevnar 13 and Merck's Pneumovax 23 are the franchise dominant vaccines that contain 13 and 23 serotypes of antigens against the bacterium Streptococcus in pneumococcal disease. These polyvalent vaccines, even though build protective features against as many as 23 serotypes of the bacterium, are still in progress of development as there are about 100 serotypes in total. Research has been dedicated to surfacing refined vaccines for both broader coverage, and more secure protection against the current 23 serotypes and the rest of the 100 serotypes in Streptococcus.[29] In 2021, 2 new vaccines have been launched again by Pfizer and Merck to supplement their defence against pneumococcal disease which are Prevnar 20 (PCV-20) and Vaxneuvance (PCV-15) respectively.[30] In number, Vaxneuvance covers 5 less serotypes but with the FDA-approved combination of Pneumovax 23 with Vaxneuvance, it covers more serotypes in total compared to the new Prevnar20 developed.[31] The direction vaccines are heading towards is not only for stronger protection against the current bacterium or viruses covered but horizontally, reaching out to other strains or serotypes.[6]

Warnings and precautions

While live recombinant vaccines are generally considered to be safe, there is a slight possibility that the genetically modified bacteria and viruses in the vaccine can revert back to pathogenic, causing disease in hosts, particularly in young, immunocompromised and older subjects.[32] An example of this would be the oral polio vaccine (OPV). The OPV is made of three viral strains that are all genetically modified to have low virulence, it is estimated that the risk of this vaccine causing disease is 1 in 750000 recipients.[33] However, it is found that the modified viruses are at risk of reverting back to their pathogenic state, with one serotype being three mutations away from reversal and another being two mutations away.[33] Additionally, in countries with scattered vaccine coverage, such as India and Nigeria, viruses used in OPV have regained pathogenicity, causing epidemics and even endemics.[34]

References

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  2. 1 2 "Vaccine Types". HHS.gov. Office of Infectious Disease and HIV/AIDS Policy. 2021-04-26. Retrieved 2023-03-15.
  3. 1 2 "Polio Vaccination: What Everyone Should Know | CDC". www.cdc.gov. 2022-11-03. Retrieved 2023-03-15.
  4. 1 2 3 "FluMist Quadrivalent".
  5. 1 2 Aldossary AM, Ekweremadu CS, Offe IM, Alfassam HA, Han S, Onyali VC, et al. (June 2022). "A guide to oral vaccination: Highlighting electrospraying as a promising manufacturing technique toward a successful oral vaccine development". Saudi Pharmaceutical Journal. 30 (6): 655–668. doi:10.1016/j.jsps.2022.03.010. PMC 9257926. PMID 35812139.
  6. 1 2 3 Nascimento IP, Leite LC (December 2012). "Recombinant vaccines and the development of new vaccine strategies". Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas. 45 (12): 1102–1111. doi:10.1590/S0100-879X2012007500142. PMC 3854212. PMID 22948379.
  7. ↑ "A Brief History of Vaccination". www.who.int. Retrieved 2023-03-15.
  8. ↑ CDC (2022-09-15). "14 Diseases You Almost Forgot About (Thanks to Vaccines)". Centers for Disease Control and Prevention. Retrieved 2023-03-15.
  9. ↑ "Understanding Six Types of Vaccine Technologies | Pfizer". www.pfizer.com. Retrieved 2023-03-15.
  10. ↑ Delany I, Rappuoli R, De Gregorio E (June 2014). "Vaccines for the 21st century". EMBO Molecular Medicine. 6 (6): 708–720. doi:10.1002/emmm.201403876. PMC 4203350. PMID 24803000.
  11. ↑ Carter D. "T cells, B cells and the immune system". MD Anderson Cancer Center. Retrieved 2023-03-15.
  12. ↑ "Types of vaccine". vk.ovg.ox.ac.uk. Retrieved 2023-03-15.
  13. ↑ "Attenuated Vaccine – an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2023-03-15.
  14. ↑ "History of polio vaccination". www.who.int. Retrieved 2023-03-15.
  15. ↑ "Polio live oral vaccine: Here's why the US stopped using it years ago". FOX News. 2022-07-23. Retrieved 2023-03-15.
  16. ↑ "Polio Vaccination | CDC". www.cdc.gov. 2022-08-12. Retrieved 2023-03-15.
  17. ↑ "Homepage | ROTARIX (Rotavirus Vaccine, Live, Oral) for HCPs". www.rotarixhcp.com. Retrieved 2023-03-15.
  18. ↑ "Rotavirus Vaccine Information Statement | CDC". www.cdc.gov. 2022-06-02. Retrieved 2023-03-15.
  19. ↑ "RotaTeq® (Rotavirus Vaccine, Live, Oral, Pentavalent) | Health Care Professionals". MerckVaccines.com. Retrieved 2023-03-15.
  20. ↑ "Shingrix (Zoster Vaccine Recombinant, Adjuvanted)". www.shingrix.com. Retrieved 2023-03-15.
  21. ↑ "Clinical Overview of Herpes Zoster (Shingles) | CDC". www.cdc.gov. 2022-09-14. Retrieved 2023-03-15.
  22. ↑ "Herpes Zoster (Shingles)". Gleneagles Hospital Hong Kong. Retrieved 2023-03-15.
  23. 1 2 "How Shingles Spreads | CDC". www.cdc.gov. 2022-11-28. Retrieved 2023-03-15.
  24. ↑ "Shingles Q&A: Is Shingles Contagious & Everything Else You Need to Know". www.houstonmethodist.org. Retrieved 2023-03-15.
  25. ↑ "Live Attenuated Influenza Vaccine [LAIV] (The Nasal Spray Flu Vaccine) | CDC". www.cdc.gov. 2022-08-25. Retrieved 2023-03-15.
  26. 1 2 Birkhoff M, Leitz M, Marx D (November 2009). "Advantages of intranasal vaccination and considerations on device selection". Indian Journal of Pharmaceutical Sciences. 71 (6): 729–731. PMC 2846493.
  27. ↑ "GPEI-OPV". Retrieved 2023-03-15.
  28. ↑ Mackett M (December 1987). "Recombinant live virus vaccines". Immunology Letters. 16 (3–4): 243–248. doi:10.1016/0165-2478(87)90153-2. PMID 3327813.
  29. ↑ "About Pneumococcal Vaccine: For Providers | CDC". www.cdc.gov. 2022-10-21. Retrieved 2023-03-15.
  30. ↑ Dunleavy K (Oct 4, 2021). "Merck's Vaxneuvance makes its case for an FDA Approval in children".
  31. ↑ "Ask the Experts: Pneumococcal Vaccines". www.immunize.org. Retrieved 2023-03-15.
  32. ↑ Singh BR (October 2011). "Advantages and Disadvantages of Genetically Engineered Vaccines". ResearchGate.
  33. 1 2 Bull JJ (January 2015). "Evolutionary reversion of live viral vaccines: Can genetic engineering subdue it?". Virus Evolution. 1 (1): vev005. doi:10.1093/ve/vev005. PMC 4811365. PMID 27034780.
  34. ↑ Kew O (April 2012). "Reaching the last one per cent: progress and challenges in global polio eradication". Current Opinion in Virology. 2 (2): 188–198. doi:10.1016/j.coviro.2012.02.006. PMID 22482715.
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