The Race to Reduce Covid-19 Transmission: An Update on 67 Intranasal & 6 Oral Vaccines

It’s a glaring example of a pair of problems that have plagued Covid vaccines: parochialism and failures of information management when science moves fast. An intranasal vaccine is already in use in one country – as a third dose after 2 shots. Another 5 are in, or on the brink of, phase 3 trials, and a few more are well into mid-stage of testing. Dozens of others are in development. Yet, in February, a relative latecomer to this group, Yale University, heralded their preclinical work as “a new approach”. And New York Times declared an Indian nasal vaccine might be first past the line that had already been crossed last October.

Covid protection from a squirt in the nose isn’t just around the corner for most of us. It’s not a slam dunk. One of the earliest vaccine developers that started down this road pulled out after phase 1. Another example: one of the intranasal vaccines developed by NIH groups didn’t provide rapid protection in non-human primates, even though it did when injected. But overall, it’s looking as though widespread intranasal boosters could well be on the cards, and that could be a meaningful step forward.

Intranasal and oral vaccines are mucosal vaccines. Like the coronavirus itself, they get into our bodies through the mucosal membranes in our airways – the wet linings of our nose, mouth, throat, and lungs. The goal is to set up a line of defence in those membranes, called mucosal immunity, backed up by systemic immunity – the antibodies and immunity-driving cells circulating in our blood. Mucosal immunity is often called sterilizing immunity. That’s a bit unfortunate – it implies infection is impossible, which is hoping for too much.

Protection at the source could help prevent the virus taking hold at all, though, thereby reducing transmission in the community. There are more potential benefits from nasal spray and tablet vaccines. For one, they are easier to distribute, store, and administer. Other issues on the vaccine wish list are longer-lasting immunity – mucosal immunity may be slower to wane – and better protection against variants.

Mucosal vaccines could be designed to be the sole vaccine, aiming for mucosal and systemic immunity. Or they could be part of a vaccine course that includes injections as well. The first intranasal Covid-19 vaccine to get an emergency use authorization is like that: it’s 2 injections followed by an intranasal dose. That’s Iran’s protein subunit vaccine, Razi Cov Pars, and it got the green light at the end of October 2021. As far as I know, it’s still the only one, although others could be quite close.

Before we dig in, a brief note on sources: this post draws on my tracking collection of Covid vaccines which focuses on vaccines with preclinical or clinical results, with cross-checking against the list compiled by Alu and colleagues (2022). I think this might be the most comprehensive collection there is, but it’s sure to be missing some.

The 73 vaccines are listed in detail in 3 tables at the end of the post, with links to results and trial register entries (intranasal vaxes with clinical results &/or rolled out; other intranasal vaxes with preclinical results &/or in clinical trials; and oral vaccines).

Let’s start with a brief overview of the 73 mucosal vaccines:

• Nearly 40% are being developed in the USA (28 vaccines, including the frontrunner oral vaccine and live attenuated intranasal vaccine).
• More than half internationally are viral vector vaccines.
• 1 is authorized for community use (a protein subunit vaccine in Iran).
• Another 4 are for vaccines that have injected versions authorized for community use in at least one country (AstraZeneca, CanSino, Medigen, and Sputnik V).
• 17 are in clinical trials (including the authorized Iranian vaccine, Razi Cov Pars)
  • 5 have reached efficacy trial stage (phase 3+)
  • 3 have reached mid-stage trial (phase 2)
  • 8 have reached first-in-human trial (phase 1).
• 1 is in a clinical trial for adolescents (Razi Cov Pars).
• 69 out of the 73 have released preclinical results – it’s not clear how many of these will progress to clinical trials: some had weak results, and some don’t have manufacturing partnerships.
• 1 vaccine from the US was discontinued in June 2021 after phase 1 efficacy was “substantially lower” than the vaccines already authorized there.
• Of the 6 oral vaccines, half have gone into clinical trials – 1 is in phase 2 (from Vaxart in the US), and the other 2 are at first-in-human stage (1 each from Israel and the US).

The 6 mucosal vaccines that have reached late-stage efficacy trials are listed below in alphabetical order. Some of these are going to have gathered only a fairly small amount of safety data by the end of these trials:

Vaccine	Phase	Participants	Country/ies	Vax status
Ad5-nCoV (Convidecia) Viral vector (adenovirus) CanSino (China)	3	10,420 people	China	Injected version authorized in multiple countries
	4	904 people (booster trial for ZF2001 vax)	China
BBV154 Viral vector (adenovirus) Bharat Biotech (India)	2/3 & 3	Total of 3,708 people		No authorization
	3	875 people (booster trial for Covaxin & AZ/Covishield)
CoviLiv Live attenuated Codagenix (USA)	2/3	Not yet announced – joining WHO Solidarity Trial, a placebo-controlled trial	Currently Colombia, Ghana, Philippines.	No authorization
DelNS1-nCoV-RBD-OPT1 Viral vector (influenza) Beijing Wantai Biological (China)	3	45,400 people	Colombia, Ghana, Philippines, South Africa	No authorization
GAM-COVID-VAC (Sputnik V) Viral vector (adenovirus) Gamaleya Research Institute (Russia)	2/3	1,320 people	Russia	Injected version authorized in multiple countries
Razi Cov Pars Protein subunit Razi Vaccine & Serum Research Institute (Iran)	3	41,128 people.	Iran	3-dose course (2 injected & 1 intranasal) authorized for use in October 2021

That frontrunner list gives an inaccurate impression, though, of where the mucosal vaccine candidates are being developed. As I mentioned earlier, nearly 40% are by developers in the US – and some of the vaccines being developed outside the US are iterations of US-originated vaccines. Alongside the 28 vaccines under development in the US, there are 13 in China. The rest come from 21 countries, mostly with 1 or 2 each, though Canada and South Korea each have 4.

There is enormous variety in the 73 vaccines themselves. They can be:

• designed solely for mucosal use from the start, perhaps with an adjuvant designed for the mucosal membranes;
• an intramuscular (injected) vaccine adapted for spraying or drops, for example by combining it with an adjuvant; or
• the same vaccine that’s injected simply sprayed into the nose instead.

Just over half of the vaccines are based on viral vectors. That’s the same type of technology as 3 of the top 8 Covid vaccines used internationally – AstraZeneca, J&J, and Sputnik V. Each of those, though, are based on adenoviruses: there’s more variety in this group, with quite a few based on influenza or parainfluenza virus.

Then there are 14 protein subunit vaccines, including the Razi Cov Pars. That’s the more traditional vaccine type that’s used by most of the non-profit Covid vaccines and Novavax. One of those is among the 14 here (Patria in Mexico).

The category “Other” includes 15 vaccines, of 8 different types, and they’re listed below. Only 2 involve mRNA, and neither of those are vaccines that are available as injections now – and neither is in clinical trials.

Viral vector	39
Protein subunit	14
Live attenuated	5
DNA	3
Virus-like particles	3
Extracellular vesicles	3
Bacterium vector	2
Toxoid vector	1
Peptide	1
Encapsulating mRNA	1
Replicon mRNA	1
	73

From here on in this post, you can dig around into the specific vaccines. Some things to keep in mind: some are already being tested as boosters after vaccines that are already in use. Mixing vaccines could have advantages, but it will be a key issue for regulators considering these vaccines.

Secondly, these vaccines aren’t specifically adapted for variants, but they may have advantages there nevertheless. That said, variant-adapted boosters may arrive on the scene, too. (See my February post on vaccines adapted for variants.) And finally, as ever with vaccines, safety issues are going to be critical. The ones with large phase 2 and 3 trials should amass enough data on common reactions. There are a couple, though, that are going fast, with relatively minimal study (in India and Russia). So there’s a lot to watch out for.

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Intranasal vaccines with clinical results and/or for vaccines that are already rolled out

(All records) in the first column below links to records on all forms of these vaccines.

Vaccine, type, manufacturer	Tested use	Participants	Location(s)	Research phase
Ad5-nCoV (Convidecia) Viral vector (adenovirus) CanSino (China) (All records)	2 doses intranasal CanSino or injection or 1 injection of CanSino followed by 1 intranasal; high or low dosage.	149 people.	China.	Phase 1. Results (for 130 people).
	High or low dose single intranasal dose of CanSino after 2 doses of Sinovac’s CoronaVac (inactivated vaccine); or additional dose of CoronaVac.	420 people.	China.	Phase 1/2. Results.
	Single dose intranasal CanSino (low dosage) after 2 previous injections of inactivated vaccine (CoronaVac or Sinopharm’s Beijing or Wuhan); or 3rd injection of inactivated vaccine.	10,420 people.	China.	Phase 3.
	Single dose of intranasal or intramuscular CanSino or injection of inactivated (CoronaVac) or protein subunit vaccine (ZF2001) as a booster after 2 injections of CoronaVac.	904 people.	China.	Phase 4. Results.
	Low dose intranasal CanSino followed by high dose intranasal.	10 non-human primates (macaques).	China.	Preclinical. Results.
AdCOVID Viral vector (adenovirus) AltImmune (USA) (All records)	1 or 2 intranasal doses of AdCOVID (3 dosages); or placebo.	92 people planned, but only 2 of 3 age cohorts recruited.	USA.	Phase 1. Results – press release only (vax discontinued).
	1 intranasal dose of AdCOVID	15+ mice (number unclear).	USA.	Preclinical. Results.
ChAdOx1 nCOV-19 Viral vector (adenovirus) AstraZeneca (AZ) (UK) or Serum Institute of India (as Covishield) (All records)	1 low, intermediate, or high dose intranasal AZ after previous course of Covid vax (2 injections of Moderna or Pfizer vax, or 1 injection of J&J).	15 people.	UK.	Phase 1.
	1 low, intermediate, or high dose intranasal AZ in previously unvaxed; or 1 low, intermediate, or high dose intranasal AZ after previous 2 injections of AZ or no booster; or 1 high dose intranasal AZ after previous 2 injections of Pfizer vax.	54 people.	UK.	Phase 1.
	1 or 2 doses of intranasal AZ or injection.	20 ferrets.	UK.	Preclinical. Results.
	1 dose of intranasal AZ or injection or control.	30 hamsters; 8 non-human primates (macaques).	UK.	Preclinical. Results.
CoviLiv Live attenuated Codagenix (USA) (All records)	1 dose of intranasal COVI-VAC after previous course of Covid vax (2 injections of Moderna or Pfizer vax, or 1 injection of J&J), in 3 dosages.	48 people.	UK.	Phase 1. Press release stating successful (without data) and progressing to phase 2/3. Results (conference abstract).
	Not yet announced	To be powered for 150 cases of Covid-19.	WHO Solidarity Trial – currently Colombia, Mali, Philippines.	Announcement of joining Solidarity Trial. (Protocol.)
	1 intranasal dose of COVI-VAC (plus controls).	39 hamsters.	USA.	Preclinical. Results.
GAM-COVID-VAC (Sputnik V) Viral vector (adenovirus) Gamaleya Research Institute (Russia) (All records – Sputnik V, Sputnik Light)	1 intranasal dose of either rAd26 (Sputnik Light) or rAd5, both (Sputnik V), or placebo.	400 people. (500 in phase 2 according to Russia’s trials registry, 400 in Moscow + 260 elsewhere in Russia according to media report).	Russia.	Phase 1/2.
	Compares intranasal Sputnik with injected (no further details).	1,320 people (according to Russia’s trials registry).	Russia.	Phase 3 (or phase 2/3 – not clear).
Mambisa Protein subunit Centre for Genetic Engineering & Biotechnology (CIGB) (Cuba) (All records)	3 intranasal doses of Mambisa (drops) or 1 injection of Mambisa followed by 2 intranasal doses, each in 2 dosages & 2 different intervals.	88 people.	Cuba.	Phase 1/2.
	1 intranasal dose of Mambisa drops in 2 dosages or 1 dose of intranasal spray Mambisa, or 1 injection of CIGB’s Abdala vaccine.	120 people who had recovered from Covid-19.	Cuba.	Phase 1/2. Results (press release only).
	1 intranasal dose of Mambisa or 1 injection of Abdala vaccine, after a previous 3-dose course of Abdala.	1,500 – 5,000 people.	Cuba.	Phase 2.
MVC-COV1901 Protein subunit Medigen (Taiwan) (All records)	1 intranasal dose of core component of MVC-COV1901 with nanoemulsion adjuvant after 2 previous injections of MVC-COV1901.	46 hamsters.	Taiwan.	Preclinical. Results. (See also results for the nanoemulsion adjuvant.)
Patria (NDV-HXP-S/AVX-COVID-12-HEXAPRO) Viral vector (Newcastle Disease Virus) Laboratorio Avi-Mex (Mexico) (All records on Patria, early development of NDV-HXP-S)	2 intranasal doses of Patria, 1 intranasal dose followed by 1 injection of Patria, or 2 injections of Patria, in 3 dosages.	91 people.	Mexico.	Phase 1. Results.
	1 intranasal or 1 intramuscular dose of Patria after previous course of Covid vax (AZ, CanSino, CoronaVac, J&J, Moderna, Pfizer, Sinopharm Beijing, or Sputnik V).	396 people.	Mexico.	Phase 2.
Razi Cov Pars Protein subunit Razi Vaccine & Serum Research Institute (Iran) (All records)	1 intranasal dose after 2 injections of Razi Cov Pars in 3 dosages, or adjuvant only.	133 people.	Iran.	Phase 1.
	1 intranasal dose after 2 injections of Razi Cov Pars, or adjuvant only.	500 people.	Iran.	Phase 2.
	1 intranasal dose after 2 injections of Razi Cov Pars, or injections of Sinopharm Beijing vaccine.	41,128 people.	Iran.	Phase 3. (Press report of results, in the first 24,000 participants.)
	1 intranasal dose after 2 injections of Razi Cov Pars.	210 people (adolescents).	Iran.	In 12-17 year-olds.

Other intranasal vaccines – with preclinical results and/or in clinical trial

Vaccine name	Manufacturer/developer	Vaccine type	Research phase
Ad5-N	Beijing Institute of Basic Medical Sciences (China)	Viral vector (adenovirus)	Preclinical results
Ad5.SARS-CoV-2-S1	University of Pittsburgh (USA)	Viral vector (adenovirus)	Preclinical results
Ad5-S-nb2	Guangzhou Institutes of Biomedicine & Health & Guangzhou nBiomed (China)	Viral vector (adenovirus)	Preclinical results
AdC7-RBD-tr2	Chengdu Kanghua Biological Products (China)	Viral vector (adenovirus)	Preclinical results
AdCoV2-S	National Health Research Institutes (Taiwan)	Viral vector (adenovirus)	Preclinical results
BBV154	Bharat Biotech (India)	Viral vector (adenovirus)	Phase 1 Phase 2 Phase 2/3 Phase 3 Phase 3 (See ChAd-SARS-CoV-2-S below for preclinical)
BCPIV/S-2PM	BioComo (Japan)	Viral vector (parainfluenza)	Preclinical results
BReC-CoV-2	West Virginia University (USA)	Toxoid vector (diphtheria)	Preclinical results
ChAd-SARS-CoV-2-S	Precision Virologics with Washington University in St Louis & NIAID (USA)	Viral vector (adenovirus)	Preclinical results (macaques) Preclinical results (hamsters) Preclinical results (mice) (See BBV154 above for clinical trials of Bharat version)
CNUHV03-CA22	Chungnam National University (South Korea)	Live attenuated	Preclinical results
COH04S1	City of Hope & NCI (USA)	Viral vector (Modified Vaccinia Ankara)	Preclinical results (See records for intramuscular version of this vaccine)
CuMVTT-RBD	Saiba Biotech (Switzerland)	Virus-like particles	Preclinical results
CVXGA1	CyanVac and University of Georgia (USA)	Viral vector (parainfluenza)	Phase 1 Preclinical results
GLS-5310	GeneOne Life Science (South Korea)	DNA	Phase 1 (Trials of other versions of this vaccine)
DelNS1-nCoV-RBD-OPT1	Beijing Wantai Biological (China)	Viral vector (influenza)	Phase 1 (Hong Kong) Phase 2 (Hong Kong) Phase 3 (40,000 in Colombia, Philippines, South Africa) Phase 3 (5,400 in Ghana)
ΔNA(RBD)-Flu	Fred Hutchinson Cancer Research Center & University of Washington (USA)	Viral vector (influenza)	Preclinical results
hA5-Covid-19	ImmunityBio (USA)	Viral vector (adenovirus)	Preclinical results (See records for intramuscular version of this vaccine)
LP18:RBD	Chinese Academy of Agricultural Sciences Changchun (China)	Bacterium vector (Lactobacillus plantarum)	Preclinical results
MV-014-212	Meissa Vaccines (USA)	Viral vector (RSV)	Phase 1 Preclinical results
MVA-SARS-2S	Institute of Immunology Hannover (Germany)	Viral vector (Modified Vaccinia Ankara)	Preclinical results
NDV-FLS	University of Guelph (Canada)	Viral vector (Newcastle Disease Virus)	Preclinical results
NDV-HXP-S	Icahn School of Medicine Mt Sinai (USA)	Viral vector (Newcastle Disease Virus)	Phase 1 Preclinical results (See records for intramuscular form of this vaccine – see also Butanvac & Patria in this post, as well as versions in Thailand and Vietnam)
NDV-HXP-S – Butanvac	Butantan Institute (Brazil)	Viral vector (Newcastle Disease Virus)	Preclinical results (See note above for the other versions of NDV-HXP-S)
NYVAC-KC-pfsSpike	Arizona State University & University of Iowa (USA)	Viral vector (NYVAC-KC)	Preclinical results
pQAC-CoV	University of Wisconsin-Madison & Pan Genome Systems (USA)	DNA	Preclinical results
rNDV-S	Lancaster University & Texas Biomedical Research Institute (USA)	Viral vector (Newcastle Disease Virus)	Preclinical results (See also results for other form)
rVSVSARS-CoV-2	Chinese Academy of Sciences & Shenzhen Kangtai Biotechnology (China)	Viral vector (VSV)	Preclinical results
SC-Ad6-1	Mayo Clinic & Tetherex Pharmaceuticals (USA)	Viral vector (adenovirus)	Phase 1 Preclinical results
scPR8-RBD-M2	BIOTEC, NSTDA & Chulalongkorn University (Thailand)	Viral vector (influenza)	Preclinical results
(Unnamed)	Abera Bioscience (Sweden), Vrije Universiteit Amsterdam (Netherlands) & Johns Hopkins University (USA)	Extracellular vesicles	Preclinical results
(Unnamed)	Academy of Military Sciences & Chinese Academy of Sciences (China)	Live attenuated	Preclinical results
(Unnamed)	ACM Biolabs (Singapore)	Protein subunit	Preclinical results
(Unnamed)	BioTechMed-Graz & University of Graz (Austria)	Extracellular vesicles (OMV)	Preclinical results
(Unnamed)	FARVET, Cayetano Heredia University (Peru)	Viral vector (Newcastle Disease Virus)	Preclinical results
(Unnamed)	Chungbuk National University (South Korea)	Protein subunit	Preclinical results
(Unnamed)	Georgia Institute of Technology & Emory University (USA)	Protein subunit	Preclinical results
(Unnamed)	ID Pharma & National Institute of Infectious Diseases (Japan)	Viral vector (F-deleted Sendai virus)	Preclinical results
(Unnamed)	Intravacc (Netherlands)	Extracellular vesicles (OMV)	Preclinical results
(Unnamed)	Mahidol University & Institute of Biological Products (Thailand)	Protein subunit	Preclinical results
(Unnamed)	McMaster University (Canada)	Viral vector (adenovirus)	Preclinical results
(Unnamed)	National Cancer Institute NIH (USA)	Protein subunit	Preclinical results
(Unnamed)	National Institute of Allergy & Infectious Diseases (NIAID) NIH (USA)	Viral vector (parainfluenza)	Preclinical results
(Unnamed)	Oragenics & National Research Council (Canada)	Protein subunit	Preclinical results
(Unnamed)	Shanghai Bovax Biotech & GeneSail Biotech (China)	Viral vector (adenovirus)	Preclinical results
(Unnamed)	Sichuan University (China)	Protein subunit	Preclinical results
(Unnamed)	Stanford University (USA)	DNA	Preclinical results
(Unnamed)	State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Xiamen (China)	Viral vector (influenza)	Preclinical results
(Unnamed)	Sun Yat-Sen University & Chinese Academy of Sciences (China)	Protein subunit	Preclinical results
(Unnamed)	Texas Biomedical Research Institute (USA)	Live attenuated	Preclinical results
(Unnamed)	TheraVectys & Pasteur Institute (France)	Viral vector (Lentivirus)	Preclinical results (mice) Preclinical results (mice) Preclinical results (mice, hamsters)
(Unnamed)	University of California Los Angeles (UCLA) (USA)	Bacterium vector (ΔcapB)	Preclinical results
(Unnamed)	University of Hong Kong (Hong Kong)	Protein subunit	Preclinical results
(Unnamed)	University of Hong Kong (Hong Kong)	Live attenuated	Preclinical results
(Unnamed)	University of Houston & BD Biosciences	Protein subunit	Preclinical results
(Unnamed)	University of Manitoba (Canada)	Viral vector (recombinant VSV)	Preclinical results
(Unnamed X 2)	Yale University & Xanadu Bio (USA)	Protein subunit & PACE encapsulating mRNA	Preclinical results
(Unnamed)	Yunnan Key Laboratory & IMBCAMS (China)	Peptide	Preclinical results
VSV-SARS2-EBOV	National Institute of Allergy and Infectious Diseases (NIAID) NIH & University of California Irvine (USA)	Viral vector (VSV)	Preclinical results (hamsters) Preclinical results (macaques)

Other mucosal vaccines – oral

Vaccine name	Manufacturer/developer	Vaccine type	Research phase
MigVax-101	Migvax (Israel)	Virus-like particles	Preclinical results
(Unnamed)	INSERM (France) & CONICET (Argentina)	Virus-like particles	Preclinical results
(Unnamed)	Jeonbuk National University (South Korea)	Replicon mRNA	Preclinical results (mice) Preclinical results (mice) Preclinical results (hamsters)
(Unnamed)	Vyriad & Imanis Life Sciences (USA)	Viral vector (VSV)	Preclinical results
VXA-CoV2-1/VXA-CoV2-1.1-S	Vaxart (USA)	Viral vector (adenovirus)	Phase 1 Results (35 people, press release only) Phase 2 Preclinical results (mice) Preclinical results (macaques)

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For details on how I track Covid vaccine progress, see my background post. Notes on my collection of studies are here. The collection is in a public Zotero library you can dig into here.

The first version of this post (March 30) had vaccines collected by searches up to March 29. It was updated with an additional live attenuated vaccine soon after posting.

Corrections on August 1, 2022: I had incorrectly listed Oravax as the manufacturer of the MigVax vaccine, and included Meissa’s vaccine in the table for oral vaxes.

All my Absolutely Maybe Covid-19 vaccine posts

All previous Covid-19 posts at Absolutely Maybe

My posts at The Atlantic, at WIRED, and debunking posts at my personal website.

Disclosures: My interest in Covid-19 vaccine trials is as a person worried about the virus, as my son is immunocompromised: I have no financial or professional interest in the vaccines. I have worked for an institute of the NIH in the past, but not the one working on vaccines (NIAID). More about me.

The cartoons are my own (CC BY-NC-ND license). (More cartoons at Statistically Funny.)

Data underlying the table of geographical distribution of vaccine development:

USA	28
China	13
Canada	4
Sth Korea	4
France	2
Hong Kong	2
Japan	2
Taiwan	2
Thailand	2
Austria	1
Brazil	1
Cuba	1
Germany	1
India	1
Iran	1
Israel	1
Mexico	1
Netherlands	1
Peru	1
Russia	1
Singapore	1
Switzerland	1
UK	1
	73