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• Enhancing nasal antibody responses, mucosal vaccines may prevent SARS COV19 Omicron VOC infection and transmission more effectively, enabling greater control of the pandemic and limiting the emergence of
  Professor Dr. Pranab Kumar Bhattacharya MD (University of Calcutta); FICPath; WBMES (retired)
  Published on: 21 January 2023

• Published on: 21 January 2023

  Enhancing nasal antibody responses, mucosal vaccines may prevent SARS COV19 Omicron VOC infection and transmission more effectively, enabling greater control of the pandemic and limiting the emergence of

  • Professor Dr. Pranab Kumar Bhattacharya MD (University of Calcutta); FICPath; WBMES (retired), Ex Retired Professor and Head of Pathology Department and Ex Principal of a pvt Medical College in West Bengal,india Retired From Calcutta School of Tropical M, 108 Chittaranjan Avenue, Kolkata 700073 ,West Bengal, India

  Intramuscular (i.m.) ChAdOx1 nCOV19 , trade name "covishield " vaccine of company astrazeneca and sub licensed with Serum Institute of India ( mRNA 1273 vaccine for Spike Protein /RBD) and of Bharat Biotech company's whole virion inactivated Vero cell "co vaccine" which were given to Indian population in two minimum doses( free of cost) , in India ,were remarkably effective in preventing severe COVID-19 pneumonia, ARDS and hospitalisation with all sub variants( VOC) of omicron variants of concern of SARS COV-2 ,those were circulated so far in India since 2021 March and their full dose ( two/ or precautionary 3rd doses in 27% Indians ) use being associated with declining hospitalisation , ARDS, ventilation and COVID 19 related death . However, current vaccines those are given by the Indian government's health department can provide only transient protection against respiratory SARS- COV -2 viral replications , onward transmission and continuing emergence of variants of concern, by contrast, respiratory infection with SARS-CoV-2 could induces more potent serum IGg and IGa antibody mediated ( against spike protein and RBD protein) immunity against breakthrough infections ( re- infection even after vaccination or after clinical or subclinical infection) , mucosal immune defences that could inhibit viral replication and transmission, but did not happened it so in real world . Although covishield/ or co vaccine i.m. vaccinations transi...

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  Intramuscular (i.m.) ChAdOx1 nCOV19 , trade name "covishield " vaccine of company astrazeneca and sub licensed with Serum Institute of India ( mRNA 1273 vaccine for Spike Protein /RBD) and of Bharat Biotech company's whole virion inactivated Vero cell "co vaccine" which were given to Indian population in two minimum doses( free of cost) , in India ,were remarkably effective in preventing severe COVID-19 pneumonia, ARDS and hospitalisation with all sub variants( VOC) of omicron variants of concern of SARS COV-2 ,those were circulated so far in India since 2021 March and their full dose ( two/ or precautionary 3rd doses in 27% Indians ) use being associated with declining hospitalisation , ARDS, ventilation and COVID 19 related death . However, current vaccines those are given by the Indian government's health department can provide only transient protection against respiratory SARS- COV -2 viral replications , onward transmission and continuing emergence of variants of concern, by contrast, respiratory infection with SARS-CoV-2 could induces more potent serum IGg and IGa antibody mediated ( against spike protein and RBD protein) immunity against breakthrough infections ( re- infection even after vaccination or after clinical or subclinical infection) , mucosal immune defences that could inhibit viral replication and transmission, but did not happened it so in real world . Although covishield/ or co vaccine i.m. vaccinations transiently could reduce viral transmission, vaccines with if breakthrough infections occurred showed peak nasopharyngeal viral loads similar to those in unvaccinated individuals (1,2 ).
  One study, showed that viral loads declined more rapidly in vaccines with neutralising plasma antibodies ( 2 ) but it is not yet clear whether this effect is also mediated by passive transudation of plasma antibody IGa into the nasal or other naso pharyngial respiratory mucosa, or whether intra muscular COVID- 19 vaccination can also elicit nasal mucosal responses primed by infection (as it is observed after i.m. influenza vaccination following an intranasal priming).
  Vaccine with covisheld or covaccine that induces serum IGa and IGg are mostly monomeric in nature and these antibodies are produced in the bone marrow, whereas nasal IGg and IGa are polymeric and they are produced locally by mucosal plasma cells. We all know that the polymeric nasal IGa , the antibody that plays very important role for neutralisation of any virus in the upper respiratory tract, and so passive transudation of plasma antibody if at all into the nasal mucosa is unlikely to provide long durable sterilising immunity (3).So understanding whether i.m. vaccination after COVID-19 can at all recall nasal IGa responses is an important step towards market development of nasal vaccines for SARS- COV-2 which can prevent infection and transmission of the virus .
  During worldwide circulation of SARS-CoV-2,from 2019 onward to till date multiple successive variants of concern (VOC) has genetically mutated,and emerged with high and higher Ro in the community transmission as well as immune evasion or vaccine escape phenomenon, resulting in breakthrough infection even to vaccinated people worldwide including in India also . Some Omicron sub variants appeared that are less susceptible to vaccine-induced immunity and showed high reinfection rates like B 5.2.1.7 VOC as in China, Japan , USA.but not in India ( The real data from china usually not found ) . In India, immunity is obtained to a large percentage of people by successive subclinical or clinical omicron infections and minimum two doses vaccination programs possibly provided and will provide superior protection against Omicron compared with either alone . vaccination regimes which combined both intra nasal and i.m. administration in mice induced enhanced mucosal protection against SARS-CoV-2 variants (4) .This suggests that first priming the nasal mucosa with infection or by i.m vaccine is required to induce effective intra nasal local antibody responses that may provide enhanced immunity against current and future variants. However, the cross-reactivity of nasal antibodies after infection with pre-Omicron virus is unknown.
  It is seen that commonly nasal virus-specific IGA levels also fell back to pre-COVID levels after 3 to 9 months and Omicron-binding nasal responses were particularly short-lived one .Nasal IGa responses are compartmentalised from systemic responses after vaccination, which boosted nasal and plasma IGg but had limited effects on nasal IGA.The durability of nasal antibody responses has hitherto been unclear. A Dutch study with healthcare workers found that nasal antibodies lasted maximum for 9 months after mild infection, others demonstrated rapid waning even after 3 months ( 5,6) . Neither study examined a large cohort of hospitalised patients, and findings confirm that COVID-19 can induce durable mucosal immunity. Average, nasal IGa responses disappear after 9 months and Omicron-binding IGa is particularly short-lived. Nasal IGa is the most abundant mucosal antibody and provides an important first-line defence against respiratory infection. What this author want to say is that i.m. vaccination can also boost nasal IgG, but it has limited effects on IgA, that i.m vaccination only transiently boosts nasal IgA. mRNA vaccines tend to induce stronger circulating antibody responses than those using adenoviral vectors, but this may not apply to nasal responses. Taken together this author suggest that i.m. vaccination after COVID-19 is unlikely to recall mucosal responses, and nasal IgA responses, especially those to Omicron, are more short-lived and are not substantially affected by vaccination. There is lack of long-term sterilising immunity after previous infection and/or vaccination and it highlight the need for mucosal vaccines that target nasal IgA responses. By enhancing nasal antibody responses, mucosal vaccines might prevent infection and transmission more effectively, enabling greater control of the pandemic and limiting the emergence of variants.

  Bharat Biotech's intranasal Covid vaccine named "Incovacc " received Indian government approval for use as a booster dose in India the country-wide mass inoculation program. It will be administered to those above 18 years old who have previous two doses of covishield or co vaccine as a booster dose and will be first made available in all private hospitals with purchase price by minimum money Rs 800/ per dose in private hospitals of India
  ( i.e. Rs 1600/ for 8 nasal drop doses 4 drops in each nostril ) and Rs 300/ ( 8 nasal drops costs government 600/ ) in government rate- A good method of huge profitable business in the name of covid- 19 omicron sub VOC . It will also be available on CoWIN app . Few weeks back on 1st December 2022, it had got approval from the Central Drugs Standard Control Organisation( CDSCO) for restricted use in emergency situations in the age group of 18 and above. The government in a release on December 1 had called it "World’s first intranasal covid vaccine. Bharat Biotech ,"Incovacc " is a "recombinant replication deficient adenovirus vectored vaccine with a pre-fusion stabilised spike protein." It stimulates a broad immune response – neutralising IgG, mucosal IgA, and T cell responses( ??), it says. It also triggers immune responses at the site of infection (in the nasal mucosa) – essential for blocking both infection and transmission of Covid-19. Phase 3 clinical trial done in 3000 participants, Incovacc has been shown to generate good immunity following 2 doses given 4 weeks apart.Headache, Fever, Running nose, Sneezing were reported as likely side effects, while severe allergic reaction was said to be "rare."

  References
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  Effect of covid-19 vaccination on transmission of alpha and delta variants.
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  2).Singanayagam A. Hakki S. Dunning J. et al.
  Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study.
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  3)Wang Z. Lorenzi J.C.C. Muecksch F. et al.Enhanced SARS-CoV-2 neutralization by dimeric IgA.Sci Transl Med [Internet]. 2020; (Available from:)eabf1555
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  4) .Mao T. Israelow B. Peña-Hernández M.A. et al.Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses.
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  5) Fröberg J. Gillard J. Philipsen R. et al.
  SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms. Nat Commun. 2021; 12: 5621

  6)Cagigi A. Yu M. Österberg B. et al.
  Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination.
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  Conflict of Interest:
  None declared.

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