DR. EDSEL SALVANA
CLINICAL MATTERS
It is now over two weeks from the lifting of mask mandates indoors. As expected, cases are up by about 43 percent. This is from less than 1,000 cases a day the week before to 1,296 through the week of Nov. 7 to 13. During this period, there were only six new severe or critical cases, which made up a mere 0.07 percent of all the new cases. Healthcare utilization remains below 30 percent. Deaths per day, once adjusted to the actual date of death remain quite low at three to six deaths per day. After having cried wolf too many times, most social media and mainstream media pundits are watching carefully before reacting.
While many doomsayers kept predicting Armageddon with the arrival of the XBB variant coincident with the lifting of indoor mask mandates, the scientifically-sound expectations were far more nuanced. With a high rate of vaccination coupled with widespread hybrid immunity, it is unlikely that any new variants will be able to completely evade the effect of our current vaccines. Study after study shows that even the old monovalent vaccines with at least one booster continue to protect against severe disease, regardless of the predominant circulating variant.
The caution as well as the anxiety that attends any loosening of restrictions is the possibility of precipitating a spike in community transmission that disproportionally affects the most vulnerable populations. High case numbers, even with low case fatality rates, are not completely innocuous. Having to isolate for seven days has an economic impact on work and school. Mild Covid-19 can still exacerbate preexisting illness. Finally, the impact of long Covid-19 should not be underestimated. Therefore, relaxing mask mandates still comes at a cost, especially when more transmissible variants are circulating.
Fortunately, most people have kept their masks on, at least in Metro Manila. After two years of continuously wearing these, many feel naked without a mask on. We do expect that more and more people will remove their masks over time, especially when endemicity is declared. We therefore need new interventions to compensate for the expected rise in transmissions as preventive measures are further relaxed. Multivalent vaccines and new vaccine platforms can help mitigate this risk.
Bivalent vaccines are already being used in many countries. The latest studies looking at real-world data are quite promising. Moderna recently reported that neutralizing antibody activity against the circulating variants BA.5 and BQ.1.1 was significantly higher in bivalent vaccine recipients compared to those who got monovalent vaccines. This will likely also translate to better protection against infection against any new variants that arise since the genetic distance between the updated vaccines and future variants will be less compared to the ancestral strain. The World Health Organization (WHO) has not yet given a recommendation for using bivalent vaccines over monovalent ones as boosters due to the lack of data showing improved clinical outcomes. This does not mean that bivalent vaccines will not be better. All indications are that they likely will be superior. The studies that will show this conclusively, however, are still ongoing. There seem to be no additional safety issues with bivalent vaccines, and so they are thought to be just as safe as the monovalent ones.
Multivalent vaccines, which cover multiple Covid-19 variants are also coming. Both bivalent and multivalent vaccines can be updated quickly if there is evidence of loss of efficacy against infection or severe disease. Just like vaccines against human papillomavirus (HPV), which can cover up to nine different HPV genotypes, multivalent Covid-19 can target a spread of viruses from different lineages and provide broad protection against new variants. Many researchers are utilizing vaccine targets beyond the spike protein, which are less likely to mutate. This will help prevent the loss of efficacy against infection from future variants. This represents a higher technological barrier to hurdle. It may take some time for these efforts to bear fruit.
Looking at the vaccine landscape through the WHO Covid-19 vaccine tracker, there are 172 vaccines in clinical development and another 199 in preclinical development as of Nov. 11. While we are already familiar with mRNA vaccines (Pfizer, Moderna), inactivated vaccines (Sinovac, Sinopharm), viral vector vaccines (Astra, Janssen, Sputnik), and protein subunit vaccines (Novovax), there are many more platforms in development. These include virus-like particles, which are constructs of protein and nucleic acid that are known to elicit powerful immune reactions. This has been used successfully in the HPV vaccine.
Another platform is using live attenuated virus, which best mimics the natural immunogencity pathway of Covid-19. There are also many innovations on nucleic acid vaccines, including the use of DNA vaccines and mechanisms for limited replication using co-administered enzymes. Other novel and combination approaches are being tried as well.
Alternative routes of administration are also being explored. Aside from the usual intramuscular injection, subcutaneous and intradermal routes are being explored as there are more antigen presenting cells (the cells that first alert the body that there is a foreign invader) in these areas. Oral and inhaled routes are being studied as well.
There are already four approved intranasal Covid-19 vaccines from four different countries (Iran, India, China, Russia). Unfortunately, there is no clear published phase 3 data on these vaccines, and so it is difficult to determine whether they actually work. Intranasal vaccines have two major advantages over conventional injected vaccines, especially with respiratory viruses: the intranasal route mimics the pathogen route of infection and may offer the potential to trigger mucosal immunity. What’s more, these need not be injected.
An intranasal influenza vaccine has been available in the market for years now, but it has shown mixed results. An effective intranasal vaccine for Covid-19 is very desirable because it has the potential to interrupt transmission. While injected vaccines generate two major types of antibodies (IgM and IgG), which are usually found in the blood, intranasal vaccines can generate a third type of antibody, IgD, which is found in mucosal secretions and can neutralize viruses that are just trying to gain entry. Published preclinical and early phase data from some of the current intranasal vaccines do show IgD being generated. We do not know, however, if this is in high enough levels to protect against Covid-19 infection until the appropriate clinical data has been collected.
Even as SARS-CoV-2 continues to mutate, we are not helpless. Continuing to use masks and ramping up booster coverage will accelerate the end of the pandemic. In the meantime, researchers are not standing still and are readying the next volley of weapons against future iterations of Covid-19. It is an arms race against the virus to ensure we have the best tools to fight this pathogen that has already claimed so many lives.