By Lambert Strether of Corrente.
As readers know, I stan for Covid nasal sprays, whether as prophylactics or vaccines (see here and here, plus many mentions in Links and Water Cooler). So I figured it was time for another look, because “science is popping.” I should say right away that the headline is a bit deceptive. The elephant in the room is that India’s Bharat Biotech, a major contract vaccine manufacturer, will be launching its own nasal vaccine, iNCOVACC (BBV154), tomorrow, January 26, on Republic Day. However, that story has so many imponderables — including, last I checked, missing clinical trial results in journals where I would expect to find them — that I feel it deserves a post of its own when matters are a bit more sorted.
Here is the problem statement. This is the problem that nasal vaccines are meant to solve (and nasal prophylactics to ameliorate). From Cell (pre-proof), “Upper respiratory tract mucosal immunity for SARS-CoV-2“:
Early control of SARS-CoV-2 infection and prevention of transmission are heavily dependent on robust mucosal immune responses in the upper respiratory tract (URT). However, current licenced SARSCoV-2 vaccines induce predominantly systemic responses, rather than potent, durable responses in the URT mucosa. Thus, despite their effectiveness in reducing disease severity, hospitalisation rates and mortality, these vaccines do not generate sterilising immunity, thereby having a limited role in preventing infection and blocking subsequent viral transmission. Suboptimal vaccine-induced immunity that does not adequately inhibit transmission in the community, hence permitting ongoing cycles of viral replication, can promote the establishment of new, highly virulent, vaccine-resistant SARS-CoV-2 variants. Although current licenced vaccines may be effective against severe disease and death, even if to variable degrees, against some SARS-CoV-2 variants of concern (VOC), the VOC demonstrate an aptitude for immune escape with significantly reduced sensitivity to antibody neutralisation. Further, while Omicron-adapted bivalent vaccines can increase the breadth of neutralisation of different SARS-CoV-2 strains systemically, suggesting this approach may mitigate the impact of Omicron BA.4/5 as well as new emergent VOC, transmission cannot be prevented without the induction of URT mucosal responses.
Which pretty much describes where we are, doesn’t it? And where we would like to be. Indeed, it’s an exciting time to be a mucosal immune response enthusiast! The most interesting and encouraging news is that we now have a mechanism for how Covid — which is airborne, needless to say — infects the body through the nose, and to that I now turn.
The Science: SARS-CoV-2 Infects Us Through the Nose
December 2022 and especially January 2023 saw a drumfire of publications on what a layperson would call nasal infection (or, as we like to say, “replication in airway epithelia”). This article in Cell by Wu et al. (noted in Water Cooler on January 10) was especially impressive:
Using primary nasal epithelial organoid cultures, we found that the virus attaches to motile cilia via the ACE2 receptor. SARS-CoV-2 traverses the mucus layer, using motile cilia as tracks to access the cell body. Depleting cilia blocks infection for SARS-CoV-2 and other respiratory viruses. SARS-CoV-2 progeny attach to airway microvilli 24 h post-infection and trigger formation of apically extended and highly branched microvilli that organize viral egress from the microvilli back into the mucus layer, supporting a model of virus dispersion throughout airway tissue via mucociliary transport. Importantly, Omicron variants bind with higher affinity to motile cilia and show accelerated viral entry. Our work suggests that motile cilia, microvilli, and mucociliary-dependent mucus flow are critical for efficient virus replication in nasal epithelia.
(Note that “24 h post-infection” which will become important later.) Here is a graphical abstract that illustrates the process of infection:
This is important because at long last we have a mechanism of infection; now we can say not only that “covid is airborne,” we can trace its path into the body (which presumably will be of great help to all the vaccine developers out there). To translate Cell into English, “Scientists pinpoint the routes taken by SARS-CoV-2 to enter and exit cells in our nasal cavity” explains the ingenious and fascinating laboratory techniques Wu et al used, all well worth a read, and concludes:
The findings identify new targets for a nasally applied drug that, by impeding ciliary motion or microvilli gigantism, could prevent even unknown respiratory viruses — the kind you meet, say, at a pandemic — from making themselves at home in your nose or throat.
[Co-author Peter] Jackson said substances used in these experiments could perhaps be optimized for use in, say, nasal sprays soon after a respiratory viral exposure, or as prophylactics.
“Delaying viral entry, exit or spread with a locally applied, short-duration drug would help our immune systems catch up and arrive in time to stop full-blown infection and hopefully limit future pandemics,” he said.
(Note that Jackson’s vision for a “nasally applied drug” does not include vaccines, nor does the Stanford press release describing the work; but that may be product-driven; although a “morning after” nasal spray sounds like a good idea.)
However, a mechanism for nasal infection raises the possibility of a “sterilizing vaccine”[1], in essence eliminating the necessity for both CDC’s “red map” and its “green map” (as well as regular injections into muscle). From The Mail, in January 2023:
Muhammad Munir, a professor in virology and viral zoonoses at Lancaster University, believes nasal vaccines offer a solution as they ‘halt community transmission’ — in other words, stop people getting ill with Covid and passing it on.
Professor Munir says that’s because Covid enters the body via infected droplets [sic] hat gain entry mainly through the nose or mouth, the logical approach is to focus the immunological fight there. As he explains, vaccines given into the arm produce T-cells (which knock out infected cells) and B-cells (which produce antibodies that attack invading pathogens).
‘But these immune cells are predominantly in the bloodstream and organs, with only a tiny quantity in the nose and mouth so they aren’t guarding the point of entry.
‘And yet for Covid the route of transmission is through the nose and mouth. This area is lined by a mucus membrane that continues to the gut and is enriched with an armoury of immune cells.
‘If a vaccine is inhaled or given as drops through the nose or mouth then it will prime these cells, which are the first line of defence, to act quickly.’
And now comes the “24 h” part–
T-cells and B-cells in the mucosal layer can prompt a lightning-fast attack ‘pretty much the instant the virus comes in’, attacking it before it has a chance to infect cells, he says. ‘These nasal immune cells get to work in a couple of minutes — whereas the immune cells made by intramuscular vaccines get to work six to eight hours after entry of the virus.’
This time difference, he says, is vital. ‘If just one virus particle successfully sticks to one cell it takes over that cell and replicates to produce a million more viruses in an eight-hour cycle,’ says Professor Munir, who has been leading the research into Lancaster University’s nasal vaccine.
‘That’s why the nasal vaccine will have the advantage — the immune cells it produces in the nasopharyngeal region can act immediately. It’s a bit like having the police sitting and waiting for a crime to be committed.
‘With the intramuscular vaccine approach, the police only come once the problem is there, and by that time damage could be done.’
However, it would only be fair to say that nasal vaccines face challenges. From Cell, also in January 2023, “Rethinking next-generation vaccines for coronaviruses, influenzaviruses, and other respiratory viruses“:
Past unsuccessful attempts to elicit solid protection against mucosal respiratory viruses and to control the deadly outbreaks and pandemics they cause have been a scientific and public health failure that must be urgently addressed. We are excited and invigorated that many investigators and collaborative groups are rethinking, from the ground up, all of our past assumptions and approaches to preventing important respiratory viral diseases and working to find bold new paths forward.
Here is a table summarizing these challenges:
They conclude:
Taking all of these factors into account, it is not surprising that none of the predominantly mucosal respiratory viruses have ever been effectively controlled by vaccines. This observation raises a question of fundamental importance: if natural mucosal respiratory virus infections do not elicit complete and long-term protective immunity against reinfection, how can we expect vaccines, especially systemically administered non-replicating vaccines, to do so? This is a major challenge for future vaccine development, and overcoming it is critical as we work to develop “next-generation” vaccines.
Harsh, but fair. Of all the points, I will address only #4 (“Vaccine-related questions of route of administration, antigen configuration, adjuventation, and association with adjunctive therapy are of great importance in current research”). I would also remind readers that engineering advances can happen before science comes along to back them up.
Advances in Nasal Vaccine Administration
Here too the science is popping. Another article from January 2023, in Nature, “Biomaterials for intranasal and inhaled vaccine delivery“:
Once administered, respiratory vaccine formulations need to overcome various airway barriers to achieve protection (Fig. 1). The mucus lining the airway acts as a semi-permeable barrier to inhaled materials, and foreign material is usually rapidly cleared by motile cilia on the epithelial surface of the respiratory tract. Depending on their size and surface chemistry, vaccine nanoformulations consisting of nucleic acids, lipids, polymers, proteins and/or entire viruses can be trapped within mucus following inhalation. For example, adenoviral vectors used in the development of vaccines against SARS-CoV-2, HIV and tuberculosis can adhere to mucus, limiting the ability of the virus to reach target cells (for example, pulmonary dendritic cells) to elicit robust mucosal immune responses. Non-viral vaccine platforms, such as lipid-based mRNA vaccines, can be designed to overcome the mucus barrier, and may thus allow respiratory vaccination. For example, an inhaled nanoparticle vaccine coated with polyethylene glycol (PEG) can rapidly penetrate the mucus barrier and enhance the proliferation of antigen-specific T cells in the lungs and lymph nodes, as compared with intramuscular delivery of a carrier free vaccine.
So, now that we know that understanding mucus is important, we’re understanding it.
Poor Clinical Trial Results are Said to Be a Barrier
From CBS, “COVID-19 vaccines: From nasal drops to a redesign, what 2023 could have in store“:
A few of these vaccines have been licensed in other countries, but none in the U.S. — and the data behind them isn’t robust, said Dr. John Beigel, associate director for clinical research at the National Institute of Allergy and Infectious Diseases.
Even if Congress had granted the Biden administration’s request to pour resources into developing potential next-generation mucosal vaccines to broad clinical trials, Beigel said it would be challenging to “pick the winners” for government backing. .
Different companies have researched mucosal vaccines for COVID, but the data is small and fragmented, Beigel said, using different methods and benchmarks. This makes it difficult for scientists to compare early results from labs that have tried out new vaccines in animals.
“It is also not at all clear from well-controlled clinical trials that administering existing vaccines by the intranasal route (as some countries have already even approved) will provide truly meaningful benefit over the existing generation,” wrote the authors of a viewpoint co-authored last month by Dr. Peter Marks, the FDA’s top vaccines official.
All of which argues for, at a minimum, funding — and at a maximum, a second Operation Warp Speed, as advocated by Eric Topol here. I mean, asking Pfizer, Moderna, or AstraZenaca to invest in a nasal vaccine that could be sterilizing — instead of demanding endless rounds of injections by trained personnel at medical facilities — is a bit like asking Gillette to engineer a self-sharpening razor blade suitable for lifetime use, isn’t it?[2]
Conclusion
Eric Topol wrote in 2021:
I still cannot understand why intranasal vaccines have not been given top priority, given their remarkable allure to block Covid transmission; an excellent explainer for why and status @ScienceMagazine https://t.co/2T3cFElaXY
w/@ScienceVisuals pic.twitter.com/6VHG90kbc8— Eric Topol (@EricTopol) July 26, 2021
And in 2022:
[Topol] said nasal vaccines are our best shot to block infections. Those spray vaccines are effective in the very place where virus-laden aerosols enter the body. They’re already being used in India and China.
“I’m confident we will have nasal vaccines that work. The only question is, do they work for a few months or is it longer,” Topol said. “It should work against all of the variants. And this is something that is very exciting; the ability to block infections and the whole chain of transmission.”
Without giving details, Topol said he expects to see some news from health officials about nasal spray availability in the weeks ahead.
That was December 20, 2022. So the “weeks ahead” have come and gone. What’s the matter: Biden not “thinking” about them? Maybe nasal vaccines would impede his policy of mass infection? We can’t take that chance!
NOTES
[1] From Immunity, “Sterilizing immunity: Understanding COVID-19“: “If the pathogen is eliminated before it can replicate, natural and vaccine-induced immune memory can prevent the establishment of the infection, mediating sterilizing immunity. Sterilizing immunity protects the individual and prevents transmission to new hosts, thereby contributing to protection at a population level.”
[2] Much has been made of Gillette’s AstraZenaca’s poor results with repurposing their intramuscular vaccine for nasal use. From JAMA:
Simply updating the existing vaccine constructs with new variant sequences or even making trivalent or quadrivalent vaccines covering several variants is not likely to provide the depth and breadth of protection needed to interrupt viral transmission during a prolonged period. It is also not at all clear from well-controlled clinical trials that administering existing vaccines by the intranasal route (as some countries have already even approved) will provide truly meaningful benefit over the existing generation of COVID-19 vaccines. Such limitations were recently illustrated by the disappointing results with a viral-vectored vaccine administered intranasally in an early-phase clinical trial.
See above on administration.
