2 August 2022 Episode 278: Follow up on novel vaccine concepts: mucosal application and broadening towards “pansarbeco”

Episode 278: Follow up on novel vaccine concepts: mucosal application and broadening towards “pansarbeco”

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First, this very didactic overview, provided by Patrick Smits  (see Ep 278-1 for more details)

 

 

The rest of this Episode is complex and therefore I write an introduction.  There are two major tendencies

Par 1: Developping mucosal vaccines, because the present intramuscular vaccines do not provide enough protective immunity at the site of infection and primary disease (= respiratory tractus).

Par 2:  Developing pansarbeco vaccine= broadening the vaccinal response beyond the SARS-CoV-2 variants, aiming to develop a vaccine that ideally could protect against new emerging viruses from the “SARS-like beta Coronaviruses family” (pan-Sarbeco), including related animal viruses.

In Par 1, we start with the recent Tang paper (Ep 278-2), showing that both antibody and T cell responses after intramuscular mRNA vaccination are suboptimal at mucosal sites.  However, they can efficiently be boosted by an intranasal recombinant human Adenovirus-5, expressing Spike, but NOT by a Spike protein with a particular adjuvant.

In a comment by Eric Topol (Ep 278-3), the field of intranasal COVID immunization is put into perspective, with a handful forerunners that are heading towards clinical trials.

1. Astra-Zeneca’s chimp adenoviral vector can also efficiently be used for intranasal vaccination, both in Syrian hamsters and in macaques (Ep 278-4). In hamsters, intranasal AZ vaccination lowers respiratory viral replication after challenge more effectively than the “classical” intramuscular route, protecting against disease of infected animals and blocks transmission to naïve animals.

 

2. Britany Hartwell (Ep 278-5) shows that intranasal immunization with lipid-conjugated protein  is superior to protein only in eliciting both systemic and mucosal immune responses in mice and macaques, but data on protection against challenge are not provided.

 

3. Finally, Susan Johnson (Ep 278-6) studies an oral adenoviral vaccine (VXA-CoV-2-1) in humans: it induces mucosal neutralizing antibodies that are superior to those in convalescent subjects 

 

Par 2 starts with a “policy” comment by Jon Cohen (Ep 278-7) on the low development of pansarbeco vaccines.  There are vary divergent approaches:

 

1. Gordon Joyce (Ep 278-8) uses genetically modified SARS-CoV-2 ferritin nanoparticle and elicits broad SARS coronavirus immunogenicity in mice: induction of antibodies that neutralize both SARS-CoV-2 variants and SARS-CoV-1 in vitro and in vivo (passive transfer)

 

2. Alexander Cohen (Ep 278-9) takes the “mosaic” approach, including spike Receptor Binding Domain (RBD) of SARS-CoV-2 and of 7 animal Sarbecoviruses into nanoparticles (NP).  This vaccine as an intramuscular prime-boost in mice: 

- elicited equivalent neutralization titers against several SARS-CoV-2 variants (including omicron)

- protected against both SARS-CoV-1 and SARS-CoV-2 challenge

 

3. Tianyang Mao (Ep 278-10) uses an intramuscular mRNA prime and a intranasal boost with either unadjuvanted spike protein OR spike mRNA in poly-amino co-ester (PACE) in mice

• to elicit mucosal immune memory within the respiratory tract with robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa,
• protecting mice in vivo with partial immunity from lethal SARS-CoV-2 infection

 

4. Finally Kevin Ng (Ep 278-11) focuses on the cross-reactive immunity by the S2 domain of SARS-CoV-2: intraperitoneal vaccination with “membrane bound Spike S2” in mice

• Induces in vitro neutralizing Ab against a broad range of human and animal beta CoV
• Provides in vivo protection in mice

 

 

Par 1: The need and the approaches  to develop mucosal immunization

Ep 278-2: Jinyi Tang Sci Immunol July 2022 Need for mucosal vaccination to optimize lung immunity

Fig 2: Intramuscular COVID mRNA (or Adeno 26 J&J) vaccinated individuals exhibit lower respiratory neutralizing antibody responses compared to convalescents, while plasma neutralizing Ab are similar (note BAL= broncho-alveolar lavage)

 

 

 

Fig 3: B, CD4 and CD8 T cell responses to Spike are very weak in the respiratory tract (broncho-alveolar lavage fluid or BAL) after intramuscular mRNA vaccination, while very robust after infection (= convalescent subjects).

 

 

 

 

Fig 4: Combination of mRNA plus mucosal adenovirus immunization induces high levels of mucosal

neutralizing activity against SARS-CoV-2 Omicron BA.1.1

 

 

 

Remark: The intranasal boost with Spike recombinant Adenovirus 5 (Ad5-S) is clearly superior to intranasal Spike trimer plus cGAMP adjuvant (S-trimer with cGAMP)   

 

Ep 278-3: Comments by Eric Topol and Akiko Iwasaki on the Tang paper

 

A major unmet clinical need has arisen

• to block the transmission chain,
• prevent the frequent breakthrough infections,
• and achieve high levels of durable protection against severe disease, no less prevent post-acute sequelae of SARS-CoV-2 infection (PASC, Long COVID-19).

 

(As we will see in Ep 278- 4, intranasal (IN) vaccination has the potential to block transmission probably better than

intramuscular (IM)

 

Fortunately, there are at least 12 nasal vaccines that are in clinical development and four have reached Phase 3 randomized, placebo-controlled trials:

• 3 are viral vector (Bharat Biotech, Codagenix and Beijing Wantal Biological), using a recombinant spike protein or receptor-binding domain or a live, attenuated virus;
• a 4th is a protein subunit vaccine (Razi Vaccine and Serum Research Institute).

 

Of these, Codagenix has announced positive results via a press release of a strong cellular immune and mucosal antibody response versus Omicron BA.2  Codagenix press release, https://codagenix.com/codagenix-intranasal-COVID-19-vaccine-shows-potent-cellular-immune-response-against-conserved-viralproteins-indicating-potential-for-immunogenicity-against-omicron-and-futurevariants-in-phase-1-dat/

 

Hereafter, I will summarize some of the recent publications on intra-nasal and also one on oral vaccination.

 

 

Ep 278-4: Neeltje van Dorenmalen Sci Transl Med Nov 2021: The intranasal (IN) application of the Astra-Zeneca vaccine ChAdOx1 nCoV-19/AZD1222 reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models

 

1. IN (intranasal) ChAdOx1 nCoV-19 vaccination superior to IM (intramuscular)  in Syrian hamsters

 

Fig. 1. Direct effect on SARSCoV-2 infection and disease

 

 

 

In C the animals were challenged with live virus: the controls (green) get ill (lose weight), while IN or IM vaccinated animals are protected

 

 

Oropharyngeal viral infectious titers (TCID50) in the days post infection (DPI) is clearly lowest in the IN vaccinated hamsters as compared to IM vaccinated and non-vaccinated controls

 

Fig. 3. Indirect effect on transmission in hamsters

 

 

 

 

Animals to be co-housed with infected animals were either IN vaccinated or IM vaccinated or not (= controls)

 

In the days post exposure (DPE), the control animals lose weight and have higher infectious titers in the oropharyngeal swabs than the vaccinated, with IN vaccinated showing lowest viral titers.

 

2. Fig 5.  IN ChAdOx1 nCoV-19 vaccination protects Rhesus macaques from productive infection

 

 

Amount of genomic RNA and subgenomic RNA in nasal turbinates (E) and lung tissue (F) is shown.

(subgenomic RNA = indication of viral replication)

For all panels, blue indicates vaccinated animals and purple indicates control animals.

 

Ep 278-5: Britany Hartwell in Sci Transl Med July 2022 shows that intranasal immunization with lipid-conjugated protein  is superior to protein only in eliciting both systemic and mucosal immune responses

 

The protein used is either SARS-CoV-2 receptor binding domain – RBD in mice (Fig 5) or HIV Envelope eOD = eOD-GT8 (gp120 engineered outer domain–germ line–targeting immunogen 8) in macaques (Fig 6)

 

  

 

 

Remark: These are very nice data, showing that intranasal protein is immunogenic in this format, but there is no direct comparison with mRNA and results are less spectacular in the macaque as compared to the mouse model.

 

 

Ep 278-6: Susan Johnson medRxiv 19 July 2022 Oral adenoviral vaccine (VXA-CoV-2-1) induces mucosal neutralizing antibodies that are superior to those in convalescent subjects 

 

VXA-CoV-2-1 =  tablet vaccine comprised of a non-replicating adenoviral vector expressing the SARS-CoV-2 Spike and Nucleocapsid genes and a double-stranded RNA adjuvant.

 

 

Nasal and saliva samples were tested for their ability to inhibit binding of ACE-2 to RBD

in a surrogate viral neutralizing test (sVNT).

 

Fig 3G:  50% of the vaccinated cohort displayed more surrogate neutralizing activity of nasal IgA than the convalescent subjects. Similar responses were seen with the saliva samples, with the VXA-CoV2-1 subjects showing higher responses.

 

 

 

 

Fig 4 A/B: About 50% of this inhibitory activity in responders was maintained over time in both the

nasal and saliva with most subjects having a higher surrogate neutralizing capacity 6

months post vaccination than pre-vaccination.

Several subjects had an increase, most likely being boosted by natural exposure to SARS-CoV-2 or other coronaviruses

 

Fig 4C Cross-inhibitory activity was also shown against SARS-CoV-1, with an average of 64% cross-inhibitory activity shown compared to the SARS-CoV-2 sVNT assay

 

 

 

 

 

Par 2: Towards a broader pan-sarbeco (SARS-like beta coronaviruses) vaccine?

 

Ep 278-7:  Jon Cohen discusses the slow progress towards a broader vaccine.  Several US groups are working on this principle (see below), but the sense of urgency is no longer present and funding is limited….

 

Ep 278-8: Gordon Joyce Cell Rep Dec 2021 SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity

 

 

By iterative structure-based design, four categories of engineered SARS-CoV-2 ferritin nanoparticle were generated

That recapitulate the prefusion SARS-CoV-2 spike, S1, and RBD.

 

These immunogens induce robust and protective neutralizing antibody responses against SARS-CoV-2 and elicit potent neutralization against variants of concern and the heterologous SARS-CoV-1

 

Schematic representation of Spike-Ferritin (SpFN)  and Receptor-Binding-Domain Ferritin (RFN) nanoparticles

 

 

Additional modifications included pCov111 and pCov146

Induction of Neutralizing Ab against SARS-CoV-2 variants of concern and against SARS-CoV-1

 

 

 

Successful passive immunization against SARS-CoV-2 challenge in mice

 

 

 

A version of this vaccine is now in human trial

 

Ep 278-9: Alexander Cohen in Science 5 July takes the “mosaic” approach, including spike RBD of SARS-CoV-2 and of 7 animal Sarbecoviruses into nanoparticles (NP).  

As compared to the monovalent (homotypic) SARS-CoV-2 NP, the  mosaic-8 NP vaccine intramuscular vaccination

• elicited equivalent neutralization titers against SARS-CoV-2 variants (including omicron)
• protected against both SARS-CoV-1 and SARS-CoV-2 challenge (while homotypic SARS-CoV-2 only protected against SARS-CoV-2 and not SARS-CoV-1.

 

 

 

 

 

 

 

 

Ep 278-10: Tianyang Mao in bioRxiv Jan 2022 uses still another approach: Prime and Spike

 

Prime = mRNA vaccine intramuscular

Spike = intranasal boost with either unadjuvanted spike protein OR spike mRNA in poly-amino co-ester (PACE)

 

• to elicit mucosal immune memory within the respiratory tract with robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa,
•  protects mice with partial immunity from lethal SARS-CoV-2 infection

 

 

 

 

 

 

 

 

 

 

 

Ep 278-11: Kevin Ng in Science Transl Med 27 July argues that the more conserved spike S2 protein (instead of the usual receptor binding S1) elicits broadly neutralizing antibodies, also against other beta-coronaviruses

 

1. Prior HCoVOC43 S–targeted immunity primes neutralizing antibody responses to otherwise sub-immunogenic SARS-CoV-2 S exposure and promotes S2-targeting antibody responses

 

2. Intra-peritoneal (i.p.) vaccination with SARS-CoV-2 S2 elicited antibodies in mice that neutralized diverse animal and human alphacoronaviruses and betacoronaviruses in vitro and provided a degree of protection against SARS-CoV-2 challenge in vivo.

 

 

PROVISIONAL CONCLUSIONS

 

1. The field of mucosal vaccination is making a remarkable progress: it seems to complement a basis vaccination with intramuscular mRNA, with higher mucosal immune responses and lower infectious virus after challenge (as a model for breakthrough infection).   Mucosal immunization of naïve animals may also prevent transmission from unvaccinated infected animals.

 

However:  

 

• The use of Adenovirus vectors is not self-evident, after rare complication of sometimes deadly bleeding and thrombosis occurred upon intramuscular vaccination with Adenoviruses
• The nasal rout has also specific risks, as it is in close contact with the brain (lamina cribrosa), especially with the use of viral vectors or inflammogenic adjuvantia.  Therefore, the oral route may be safer

 

2. Various principles seem to work to broaden the immune response towards other human or animal beta-CoV, including mosaic vaccines (to include variability of RBD in S1) as well as focusing on conserved epitopes ( in Spike S2 domain).  Published studies have mainly reported on immunogenicity and partial protection in mice.  Data on more relevant models (Syrian hamsters and macaques) are needed.

 

Best wishes,

 

Guido