Administering the AstraZeneca COVID-19 vaccine intranasally reduce viral loads

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A team of researchers affiliated with multiple institutions in the U.S. and one in the U.K. has found that administering the AstraZeneca COVID-19 vaccine intranasally to infected hamsters and monkeys reduced viral loads in nasal swabs, suggesting reduced shedding.

In their paper published in the journal Science Translational Medicine, the group describes testing they conducted with animals infected with COVID-19 and the possible implications of their work.

Many parts of the world where vaccinations against COVID-19 are widely available are currently experiencing another surge. Experts in the field suggest this is due to the arrival of new variants and wide resistance to the vaccinations. Meanwhile, the media has been reporting on so-called breakthrough infections, in which people who have been vaccinated become infected with the virus anyway.

Together, the new developments have led to calls for mask-wearing, even for people who have been vaccinated. This is because it is not yet clear if vaccinated people can infect other people, even if they have no symptoms. In this new effort, the researchers suggest that adding intranasal inoculation to vaccination efforts might help.

Currently, the vast majority of vaccines developed and in use are intramuscular, given via shots in the arm. Recently, a team at the University of Alabama noted that vaccines given intranasally would seem to make more sense, since COVID-19 is a disease of the nose, throat and lungs.

In this new study, the researchers have given an already existing COVID-19 vaccine intranasally to test animals with COVID-19 to see what would happen.

They found that administering intranasal AstraZeneca COVID-19 vaccine to infected hamsters and monkeys led to lowered viral loads on nasal swabs – an indication that giving the vaccine intranasally reduces shedding, which describes viruses released into the air when an infected person breathes, coughs or sneezes. Less shedding makes it more difficult for the virus to spread to other people.

Unfortunately, prior research has also shown that vaccines given intranasally confer immunity for a shorter period of time than intramuscular vaccination. Thus, as the team in Alabama noted, the best approach might turn out to be a combination of a shot in the arm along with a puff of mist up the nose to confer both short-term and long-term protection.


Intranasal Vaccine against Human and Animal Coronaviruses

Intranasal vaccination is one of the many methods of stimulating the immunity of mucosal organs such as oral, pulmonary, conjunctival, rectal, and vaginal mucosa [34]. There are many bacterial and viral infections, including COVID-19, which start from mucosal surfaces; hence, mucosal immunisation has garnered the interest of many researchers. In principle, intranasal vaccines are used to stimulate the mucosal immune system of the respiratory tract.

These include mucosal lymphoid tissues (MALT) of the nasopharynx (also known as the nasopharynx-associated lymphoid tissue—NALT) and the lungs (known as bronchus-associated lymphoid tissue—BALT) [35,36]. The immune cells from these MALT function in tandem with the ciliated respiratory epithelium and goblet cells to mechanically remove the pathogens through a muco-ciliary clearance mechanism. Intranasal vaccination is known to induce innate and adaptive immunities that involve antigen-specific memory T and B cells [37].

The host B cells respond to the exposure of antigens by the production of IgA, while memory T cells are responsible for long-term protection against specific disease. Intranasal vaccination using a recombinant adenovirus-based vaccine that expresses spike proteins of Middle East respiratory syndrome coronavirus (MERS-CoV) in mice led to the presence of T cells in the respiratory airway and the lungs [38]. Intranasal boosters after an intravenous immunisation against SARS-CoV in mice also showed the presence of T cells in lungs and bronchoalveolar lavage [39].

Furthermore, many studies have pointed out that a mucosal vaccine could, in fact, induce serum IgG that further enhances vaccine efficacy [40,41,42]. Many different preparations are available that include drops, sprays, powders, gels, and solid inserts.

Many vaccines against human and animal respiratory diseases have proven to be effective when administered via the intranasal route, including the influenza vaccine for humans [43,44,45]. Some vaccines are already commercialised, whereas some are still in the clinical trial or research phases. However, intranasal vaccines against coronaviruses have not been properly studied; thus, they are not vastly available, such as the recombinant adenovirus-based MERS-CoV [38], COVID-19 [46], bovine enteric coronavirus infection, FIP, and IB [22].

To date, many vaccine developers have evaluated intranasal SARS-CoV-2 vaccines in human, which include the DelNS1-2019-nCoV-RBD-OPT1 by Beijing Wantai Biological Pharmacy and the University of Hong Kong, BBV154 by Bharat Biotech, MV-0140212 by Meissa Vaccine Inc., hAd5-S-Fusion + N-ETSD by ImmunityBio, COVI-VAC by Codagenix/Serum Institute of India, CIGB-669 by the Center for Genetic Engineering and Biotechnology, and AdCOVID by Altimmune and the University of Alabama [41,47,48,49,50,51,52].

A recent study involving rhesus macaques showed promising results, where a single dose of intranasal vaccine induced neutralising antibodies and T cell responses that prevented SARS-CoV-2 infection [53]. Major keys to the success of intranasal vaccine to prevent respiratory disease are that the disease is purely respiratory, and strong mucosal immunity develops along the respiratory tract of a vaccinated individual. The innate and adaptive mucosal immune systems serve to protect mucosal cells of the respiratory tract from invading pathogens, including SARS-CoV-2, for viral replication.

For important respiratory coronaviruses, which include SARS-CoV-2, SARS, and MERS-CoV, spike proteins are of focal interest for vaccine development. A comparative study between subcutaneous, intranasal and intramuscularly delivered whole cell-killed SARS-CoV, Spike protein, and nucleocapsid vector vaccines against SARS revealed some interesting outcomes.

The whole cell-killed vaccine resulted in high serum neutralising antibodies, but not cell-mediated immune responses, which is important for controlling intracellular organisms such as viruses. Although intranasal administration of the spike protein and nucleocapsid vector produced lower serum neutralising antibodies, they significantly reduced SARS-CoV in the lungs of a murine model [54].

Similarly, a previous study that used the intranasal delivery of recombinant adenovirus-based vaccine that expressed the Spike protein of MERS-CoV showed significantly high and long-lasting S1-specific serum IgG, and the respiratory mucosal IgA [38]. This is interesting because the mucosal IgA prevents viral adhesion to the cells of respiratory tract.

In fact, initial information suggests that the BBV154 intranasal vaccine against COVID-19 could stimulate a broad immune response, including that of nasal mucosa. This has high potential for controlling the COVID-19 pandemic by blocking the early establishment of viral infection and subsequent transmission of the disease [55,56]. Therefore, many speculations have been made that intranasal COVID-19 could result in better protection compared to injectable vaccines [57,58,59].

Some coronaviruses have been successfully controlled by vaccination, but others, such as PED, are difficult, largely due to frequent genetic mutations. In veterinary medicine, an intranasal vaccine was tested to investigate its effect against the bovine enteric coronavirus in feedlot cattle. It was observed that intranasal vaccination significantly reduced the incidence and the treatment for bovine respiratory disease complex, a multifactorial syndrome was partially contributed to by bovine coronavirus [60,61].

In cats, intranasal vaccination against FIP showed conflicting results [62]. Some showed great protective capability [63], whereas others showed unsatisfactory protection [64,65]. When protection was satisfactory, an intranasal vaccine was proven to be able to stimulate broad immune responses including serum IgG, serum and salivary IgA, coronavirus-neutralising antibodies, and cell-mediated immune responses [63].

Intranasal vaccination has long been applied in IB, an important respiratory coronavirus disease of chickens. Numerous vaccines are commercially available which have been shown to be protective against the infection [66,67,68]. Furthermore, adjuvanted intranasal vaccines might be able to provide better protection compared to non-adjuvanted intranasal vaccines [68].

Intranasal Vaccination as a Way Forward

In general, intranasal vaccines have immunological and non-immunological advantages over injectable vaccines. Examples of immunological advantages are the ability to stimulate both mucosal and systemic immunities, whereas the non-immunological advantages include the ease of vaccine administration, non-invasive, less discomfort, increased safety, especially when involving individuals with blood-borne diseases, and not requiring medical personnel or even making self-administration of vaccine possible, which could save time and costs for mass vaccination [88,89].

To date, a total of 102 and 185 vaccines against SARS-CoV-2 are under clinical evaluation and pre-clinical evaluation, respectively [90]. Among the vaccines that are under clinical evaluation, 76 use the intramuscular delivery route, whereas only 7 are designed for intranasal delivery. One vaccine is designed with intramuscular priming followed by an intranasal booster, while another is as an intramuscular or intranasal vaccine.

These figures may suggest that the intranasal delivery route is not a popular choice in contemporary COVID-19 vaccine design. These vaccines use different platforms of non-replicating viral vectors, replicating viral vectors, live attenuated viruses, protein subunits, or inactivated viruses. Only one intranasal vaccine, DelNS1-2019-nCoV-RBD-OPT1, uses the replicating viral vector platform based on the influenza virus vector. Replicating vaccines are known to provide the most effective protection against viral infections compared to the non-replicating counterparts [91].

However, some concerns arise regarding the usage of intranasal replicating viral vector vaccines such as the potential to affect immune-compromised individuals, or prior immunity against the vector that could render the vaccine less efficacious, as well as the spread of vaccine virus in the population [91]. In veterinary medicine, replicating herpesvirus of the turkey vector vaccine is used to control poultry diseases such as IBD, ND, and avian influenza (AI), because it is safe and effective even in the presence of maternal-derived antibodies [92].

The development of human vaccines is challenging, because it should be safe, provide excellent protection, and have minimal side effects. The ease in vaccine delivery could be regarded as an added bonus. In pandemics, there is an urgent need to accelerate vaccine testing and the rollout of efficacious vaccines. Hence, it has been proposed that controlled human challenge trials should be conducted to replace Phase 3 clinical trials.

This approach is disputed and deemed as an act of cutting corners [93]. Some COVID-19 vaccines were approved without Phase 3 clinical trials; therefore, the approvals were seen as premature [94], and this may lead to hesitancy [95], that later leads to poor vaccine coverage and the failure to achieve herd immunity. The recently documented severe side-effects of injectable COVID-19 vaccines are regarded as an example of vaccine hesitancy.

This may be debatable; some research has suggested that side-effects such as thromboembolism do not contribute to vaccine hesitancy [96]. Some people may refuse vaccines simply because of a general lack of trust, as well as questioning the need for vaccination [95]. Even if safe and efficacious vaccines are designed in the near future, this stigma may persist. Although vaccine hesitancy and refusal have been reported in veterinary practices [97], its effect may not be as costly compared to the current pandemic situation or other human diseases [98].

COVID-19 is a respiratory disease; therefore, similar strategies that are used in controlling animal respiratory diseases could be employed, with the main aim of achieving widespread vaccination coverage. For example, using a coarse mist approach, or intranasal vaccination with live recombinant vaccine, or live mutant. Although this is actually possible, bioethical issues are of concern, particularly the effects on immune-compromised individuals and the spread of a vector in the population.

The administration of a replicating attenuated or mutant vaccine to a human and hope that the vaccine is transmitted to other individuals is ideal to attain quick and widespread vaccine coverage that ensures herd immunity. Theoretically, this approach is highly beneficial to increase vaccine coverage, especially in less wealthy countries.

This aligns well with the COVAX plan devised by the World Health Organization and the general goal to achieve health equity [99]. However, a commingling individual may lose the freedom to choose their vaccination status. Issues pertaining to making it mandatory for vaccination against COVID-19 or other diseases have been discussed [100,101,102], with the general inclination towards maintaining vaccination a choice.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300178/


More information: Neeltje van Doremalen et al, Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abh0755

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