Live attenuated vaccines virus

However, there are concerns regarding adverse effects, such as the induction of fever attributed to mRNA vaccines and pre-existing immunity against adenovirus vectored vaccines or their possible involvement in the development of thrombosis.

The induction of antibodies against the adenovirus vector itself constitutes another hindrance, rendering boosting vaccinations ineffective. Thus, whole virus particles or parts of the virus can be used for vaccines. Aluminum hydroxide adjuvants are commonly added to enhance the immune response induced by this type of vaccine, such as those for influenza virus, Japanese encephalitis, and poliovirus, which are controlled by neutralizing antibodies.

Inactivated vaccines for these viruses have been used for a long time in several countries, and are considered to be highly safe [37]. Gao et al. This vaccine induced anti-S and anti-RBD antibodies, and the serum from immunized animals showed neutralizing activity.

E, and India. This similarity may be effective for the induction of highly reactive antibodies, but the lower stability of the unfixed proteins might be a disadvantage over the formalin-treated inactivated vaccines. Taking into account the mechanism for SARS-CoV-2 entry into the host, various recombinant protein vaccine candidates have been generated by substituting amino acids or modifying cleavage sites to stabilize the trimeric structure of the S protein [39] , [40].

The immune response induced by inactivated vaccines may not be fully effective against the new variants with mutations in the RBD due to their altered antigenicity. For example, it may be necessary to update the vaccine seed viruses against several variants every year, or to make a multivalent vaccine. It was reported that a recombinant protein-based varicella zoster vaccine with AS01B adjuvant, induced cellular immunity [45].

So, by selecting appropriate adjuvants, it may also be possible to develop an inactivated vaccine against SARS-CoV-2 with broad efficacy against mutant strains. Known live attenuated vaccines include those against the measles virus, rubella virus, varicella zoster virus, and influenza virus.

The strains used for these vaccines were attenuated mainly through adaptation to cold culture conditions, or through non-human animals [46] , [47] , resulting in viruses with slower proliferation rates in the human body, compared to the wild type virus strains. Regardless of their slow replication, they can induce a strong immune response. For example, the vOka strain of the varicella zoster virus is an example of a live attenuated vaccine obtained from passages in guinea pig embryonic fibroblasts [48].

These strains are used as master donor viruses for live attenuated intranasal influenza vaccines. This phenotype is similar to that of a live attenuated influenza vaccine strain used in clinical settings. Importantly, these TS mutants showed lower pathogenicity than the wild type parent strain in Syrian hamsters. We detected a similar amount of virus in nasal wash specimens from TS- or wild type-infected hamsters, but the virus titer was significantly lower in the lungs of TS-infected hamsters than in those of wild type-infected hamsters.

Additionally, TS-infected hamsters generated sufficient neutralizing antibodies to protect them from re-infection with the wild-type virus. Whole genome sequencing of these mutants and analysis of revertant strains suggested that mutations in the nsp3 and nsp14 genes were responsible for the TS phenotype. The mutations in nsp14 were unique ones that, to our knowledge, have not been reported to be associated with a TS phenotype.

In contrast, mutations in the nsp3 gene were reported to be responsible for the TS phenotype in mouse hepatitis virus, a coronavirus that infects mice [54]. Seo et al. This cold-adapted mutant did not show a well-defined temperature sensitivity, but induced protective immunity in hACE2 transgenic mice and showed lower pathogenicity compared to the wild type virus. Recently, codon de-optimization has been used as a tool to attenuate viruses [56] , [57].

SARS-CoV-2 wild-type strains spread through droplets and replicate in the upper and lower respiratory tracts and in the lungs. In contrast, cold-adapted and TS mutants cannot do so [53]. Codon de-optimized virus strains proliferate more slowly than the wild-type strain in the human body and in vitro [57]. It is considered that these low proliferation rates contribute to the attenuated phenotype, but induce robust humoral and cellular immune responses.

The currently used mRNA vaccines and adenovirus vectored vaccines encode only the spike protein, therefore limiting the immune response against only this viral antigen. However, live attenuated vaccines can induce immunity to several viral antigens, enhancing the chances of protection. For example, it was reported that an adenovirus vectored vaccine coding for the nucleocapsid protein was effective in mice and hamsters, suggesting that T-cell responses to this protein might also contribute to protect from infection [60].

The immune response against a variety of antigens generated by live attenuated vaccines may be an advantage over the current mRNA and adenovirus vectored vaccines. Cold-adapted mutants replicate more slowly in the lower respiratory tract and lungs, compared to the wild type strain. Temperature-sensitive mutants cannot replicate at these locations. Codon de-optimized mutants show lower proliferation rates than the wild type strain, at any location.

Additionally, intranasal administration of live attenuated SARS-CoV-2 strains may stimulate the production of IgA, which is capable of preventing infection even by variant strains. The secreted IgA contributes to cross-protection against different strains of the influenza virus [63].

One study reported that systemic neutralizing antibodies, passively administered or induced by vaccination, could not protect the nasal cavity from SARS-CoV-2 infection [64].

Although live attenuated vaccines are among one of the most powerful vaccine modalities, there are several problems related to their use. The most serious problem is that there is a chance of the viruses regaining their toxicity due to mutations after vaccination.

A possible solution to this problem is to combine multiple responsible mutations. We have found mutations in different genes, such as nsp3 and nsp14 , to be responsible for the temperature sensitivity. Using these methods, it is possible to construct strains with various mutations, and thus maintain live attenuation, even when one responsible mutation is replaced by the wild type sequence.

In addition, adverse reactions due to the proliferation of the live attenuated vaccine strains in the nasal cavity should be evaluated. SARS-CoV-2 infection has been associated with the induction of cytokine storm and thrombosis [68] , [69]. Moreover, olfactory dysfunction has been reported as a symptom and sequela of COVID, although the detailed mechanism underlying it has not yet been investigated [3].

The temperature-sensitive strains that we isolated were able to proliferate in the nasal cavity as the wild-type strain, thereby potentially disrupting the epithelial tissues. Therefore, its effects need to be evaluated in detail. Smallpox is one of the most harmful infectious diseases known to affect humans [70].

Jenner isolated a less pathogenic poxvirus and revealed that infection with this virus prevented the development of smallpox [71]. This was the first live attenuated vaccine, and the smallpox virus was eradicated because the vaccine was highly effective and easily preserved, even with the resources available at the time. The orally administered vaccine against poliovirus is another live attenuated vaccine used to further reduce global polio case counts after the initial implementation of a policy to use an inactivated vaccine against poliovirus in the s [73] , [74].

Although the live attenuated oral polio vaccine is still used for the global poliovirus eradication program in some countries, it has been eventually replaced by the inactivated vaccine in developed countries. In countries where the live attenuated vaccine is still in use, its drawbacks have become more evident as the number of infected people decreases.

The live attenuated virus in the oral polio vaccine is able to replicate in the subject, and thus mutate, giving rise to vaccine-derived polioviruses VDPV that can reacquire neurovirulence and cause vaccine-associated paralytic poliomyelitis PAPP.

Although this rarely occurs, this is a serious adverse event and the number of reported cases of VDPV causing PAPP has recently caught the attention of the healthcare system. In order to avoid the occurrence of pathogenic VDPV, next-generation live attenuated viruses with safer and more stable genetic designs have been developed, and their practical implementation is expected [75].

For example, the introduction of multiple mutations, which are responsible for the attenuation mentioned above, is one of the methods to decrease the risk of reversion to a virulent phenotype. In addition, several factors involved in pathogenicity have been identified and described. For example, ORF8 has been reported to be a virulence factor associated with inflammation, and the furin cleavage site of the spike protein is important for virulence as well [76] , [77].

The combination of these mutations may contribute to develop safer live attenuated vaccines. New technologies have been developed and improved since the development of these vaccines, and a wide range of vaccine modalities are currently available.

Flu vaccines do not cause flu illness. The nasal spray flu vaccine contains weakened attenuated viruses, so that they will not cause flu illness. The weakened viruses are cold-adapted, which means they are designed to only multiply at the cooler temperatures found within the nose, and not the lungs or other areas where warmer temperatures exist.

If these problems occur, they begin soon after vaccination and usually are mild and short-lived. People sometimes faint after medical procedures, including vaccination. Tell your provider if you feel dizzy or have vision changes or ringing in the ears. Rarely, people can experience a severe allergic reaction after a flu vaccine or any vaccine ; there are about cases of severe allergic reactions per million flu vaccine doses administered and these reactions can be treated with medication.

More information about the safety of flu vaccines is available at Influenza Vaccine Safety. To receive weekly email updates about Seasonal Flu, enter your email address:. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Influenza Flu. Section Navigation. Facebook Twitter LinkedIn Syndicate. Minus Related Pages. What flu viruses does the nasal spray vaccine protect against? Attenuation can be achieved in several ways:. Live attenuated vaccines represent one of the first successful methods of vaccination.

In the 18th century, the British doctor Edward Jenner used cowpox virus to vaccinate children against the devastating disease smallpox. This vaccination strategy was based on the observation that milkmaids, who were often exposed to cowpox in their work, rarely got smallpox. Eventually cowpox was replaced by the related vaccinia virus. The vaccinia and cowpox viruses are highly related to the smallpox virus but cause minimal or mild disease in humans with a high degree of cross protection against smallpox.

Using the vaccinia virus-based vaccine, smallpox was successfully eradicated in the late s. There are numerous live attenuated vaccines currently in use. Examples of successful live attenuated vaccines are listed here. To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs. Live attenuated vaccines benefit from a long history of use for a variety of infectious diseases.

The overall strengths and weaknesses for live attenuated vaccines for viral, bacterial, and parasitic protozoan neglected tropical diseases are summarized here. Tools for the development of live attenuated vaccines vary widely based on the nature of the infectious organism. See tools tables regarding the availability of culture systems and techniques for genetic manipulation in the individual disease profiles.