Responding to new challenges: is there a need to relook and revise our COVID-19 vaccination strategy?

KEYWORDS:

• SARS-CoV-2
• variants of concern
• waning of immunity
• antigenic imprinting
• T-cell immunity

The emergence of new variants of concern (VOCs) of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2), Delta and then Omicron, has added new complexity and uncertainty to the raging pandemic, especially because of the negative impact on the efficacy of the most formidable weapon against the virus: Vaccines. Israel and many European countries have suffered from massive Omicron waves, despite having some of the highest vaccination rates in the world. Israel, which was the first country to recommend booster dose routinely and then even fourth dose for its vulnerable population, has ironically also set a new precedent in the world with a new seven-day new case average of 11,978 per million population [1–3]. This article presents our perspective on the post-Omicron scenario regarding current Covid-19 vaccines and the possible options for going forward.

1. Limitations of current vaccines

The current vaccines have done a commendable job in mitigating the raging pandemic by preventing severe disease, hospitalizations, and mortality. However, their efficacy in preventing infection and transmission is much lower [4]. Animal trials of current vaccines had already suggested that there was significantly reduced viral load in the lower respiratory tract of vaccinated animals, but there was no difference in nasal shedding between vaccinated and control animals, meaning thereby that the Covid vaccine under study, i.e. the Astra Zeneca vaccine has got a limited impact on the transmission of SARS-CoV-2 virus [5]. The ongoing surges propelled by new sub-lineages of the Omicron have further exposed and amplified this issue owing to extraordinary immune evasion by this variant.

Most of the current vaccines are based on the spike protein of the original Wuhan-hu-1 strain of the virus. Recent studies have shown that their effectiveness against infection and symptomatic disease is somewhat lower against Delta and significantly lower against Omicron than some other VOCs []. Further, studies have suggested a significant waning of protection against symptomatic Covid-19 with time [6]. A new study from Finland has shown that among the elderly (>70 years of age), the vaccine effectiveness (VE) of Pfizer’s BNT162b2 vaccine against severe Covid-19 fell from 91% (14–90 days after 2^nd dose) to 76% (91–180 days after the second dose), when studied in January 2022 onwards (when Omicron was dominant) [7]. A recent report from the UK Health Security Agency (UKHSA) has also shown that among citizens above 50 years of age, the VE (of all vaccines combined) against mortality was just 59% (25 weeks after 2^nd dose) [8]. These findings also suggest some amount of waning against severe disease and deaths. To overcome the waning phenomenon, booster doses of the existing vaccines have been employed by many countries. Immunogenicity studies indicated that booster doses of mRNA vaccines given at three or more months after the primary series elicit a robust immune response against the wild type (Wuhan) strain and the studied VOCs, with antibody titers often measuring higher after the booster dose than after the primary series [9–11]. The waning of protection against Covid-19 disease was much faster against the Omicron variant as compared to that for the Delta variant [8,12]. Thus, many countries (starting from Israel in July 2021) started recommending booster doses initially for vulnerable populations, and then ultimately for all other sections of their population. Now, 126 countries (mostly high- and upper-middle-income countries) have already issued recommendations on the booster or additional vaccination, and more than 120 have started programmatic implementation [13]. After the boosters’ deployment, the real-world VE studies have noticed a short-term increment in the effectiveness against the SARS-CoV-2 infection and disease [8,14–16].

2. Downsides of the booster strategy

Despite showing good immunogenicity and increments in short-term VE, a gradual waning in the protection was also noticed with the booster doses as data with longer-term follow-up emerged. It was shown that the VE of the booster dose dropped significantly after about 10 weeks of administration [12]. The UKHSA report also mentions waning of VE against symptomatic disease from 65% to 70% (2–4 weeks after booster dose) to just 25–40% (15 weeks after booster dose). The VE estimates for the booster dose are very similar, irrespective of the primary course received, and they are generally slightly higher in younger compared to older age groups [8]. Thus, the waning of VE after a booster almost mirrors the waning after 2^nd dose. Moreover, cases of symptomatic infection have been reported even within 22–59 days of getting a booster though most had only mild-to-moderate illness [17]. Israel, Chile, and Denmark have already rolled out the 2nd booster (4th dose) for their vulnerable population in face of the onslaught by immune evading Omicron variant, and many more countries are considering the same. But would it be enough? That is the key question in everyone’s mind right now. Repeated boosters are not sustainable if needed to immunize everyone on the planet [18]. So, there is an urgent need to work on an alternative, better strategy.

3. ‘Antigen imprinting’ and its implications for current COVID-19 vaccines

Recently, Roltgen et al. have published their work on antibody profiles with infection with viral variants and with different COVID-19 vaccines [19]. They investigated whether antibodies stimulated by mRNA vaccination (BNT162b2), including 3rd dose boosting, differ from those generated by infection or adenoviral (ChAdOx1-S and Gam-COVID-Vac) or inactivated viral (BBIBP-CorV) vaccines. They found that the viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than the variant antigens. This results in relatively decreased responses to the variant virus epitopes, compared to unvaccinated individuals infected with those variant viruses [19]. Such a mechanism of paradoxical reduced immune response in vaccinated individuals was earlier hypothesized to be the influenza virus and was called as ‘original antigen sin’ and the same apprehension was expressed concerning variants of SARS-CoV2 by the first author of this article last year [20].

Gagne et al. compared the booster dose of standard Moderna mRNA vaccine (mRNA-1273) and that of Moderna’s new Omicron specific mRNA candidate (mRNA-Omicron) vaccine in non-human primates (macaques) that received priming doses of standard mRNA-1273 vaccine [21]. Although both boosters worked well and prevented replication of the virus in lower airways, however, there was no difference in immune responses elicited by both the boosters. Following either boost, 70–80% of spike-specific B cells were cross-reactive against both WA1 and Omicron. Both vaccines elicited comparable B cell expansion, neutralizing antibodies, and protection against the Omicron variant. Thus, the study suggested that Omicron specific booster might not be better than the current vaccine when priming has been done with the original vaccine. The findings further hint toward the probable role of ‘antigen imprinting’ [22]. The same team had earlier demonstrated similar results even with the booster of Beta variant-specific vaccine [23].

Thus, the presence of antigenic imprinting with a much more drifted VOC, the Omicron has further complicated our vaccination strategy against emerging variants of Covid-19.

4. Dwindling role of T cell immunity

Conventionally, it is believed that T cell immunity plays a major role in providing long-lasting protection against viral illnesses, particularly against severe disease and death. The epitopes recognized by the T-cells are relatively conserved and less affected by the mutations in the spike antigen. However, few recent studies as depicted above have demonstrated a significant waning of two- and three-dose protection against even severe disease and deaths [7,8]. The third dose (first booster) was supposed to boost up memory T cell response and provide durable protection from severe illness versus Omicron. Furthermore, a recent, large study from the US suggests that is not the case [24]. In this trial, the VE of two doses of the BNT162b2 vaccine against the Omicron variant was 41% against hospital admission at 9 months or longer after the second dose. After three doses, VE of BNT162b2 against hospital admission due to the omicron variant rose to 85% at less than 3 months but fell to 55% in 3 months or longer [24]. The waning in protection against severe disease has gotten far more sinister implications than the mere waning in protection against infection and symptomatic disease.

We find that the memory T cell response has far more plasticity than neutralizing antibodies for dealing with any new emerging variant. Conventionally it is believed that T cells that were previously exposed to SARS-CoV-2 are the key to protection against severe disease and deaths. Leonardi et al. have put forward a new hypothesis suggesting that much of the protection against Covid-19 is not via T cells but rather through neutralizing antibodies, and immunological memory and cell priming may rather play a less significant role than anticipated earlier [25,26]. Covid-19ʹs ability to interfere with how T cells recognize their viral particles is the reason why T cell responses fail and do not make the grade. They implicate MHC downregulation by the ORF8 gene of SARS-CoV-2 allowing the virus to hide from T cells [25]. They depict SARS-Cov-2 as a lympho-manipulative pathogen which distorts T cell function, numbers, and death, and creates a dysfunctional immune response [25]. This is probably the reason why T cell responses do not suffice and are not permanent. In other words, the SARS-CoV-2 virus harms T cells, potentially undermining not just Covid immunity but immunity to other diseases.

More studies are needed before we accept the above hypothesis. However, if proven right, it may provide some serious jolts to our understanding of immune responses against the SARS-CoV-2 virus and may have some serious implications as far as protection against severe Covid-19 is concerned.

5. COVID-19 vaccines: Need to explore new options

We are currently in a very complex and unpredictable phase of the pandemic. The development of effective vaccines within a year of isolation of the virus has been a huge achievement of Science and Technology, but much more needs to be done to tackle this virus with greater confidence. We have explored a few potential options for the work ahead.

One option is to look for a novel vaccination strategy. The ‘prime-boost strategy’ is one such option where the priming is done by a highly effective mRNA vaccine that is boosted with a mucosal (intranasal) vaccine to elicit a broad immunological response with higher protection against infection and transmission than parenteral vaccines. There is a long list of intranasal vaccines under development [27]. Iwasaki et al. have shown that by using divergent spike proteins, ‘Prime and Spike’ enable the induction of cross-reactive immunity against sarbecoviruses without invoking the original antigenic sin. However, this vaccine is still in the early phase [28].

Another option is to develop variant-specific COVID-19 vaccines. Few vaccine companies have already started developing an ‘Omicron-specific’ vaccine to offer more robust protection against the new, highly immune evasive variant. The recent animal trials have suggested that they may not add much to the efficacy overall [21,22,29]. However, despite the probable negative impact of ‘antigenic imprinting,’ we need to update our vaccines. It is primarily to broaden immunity, which is critical. By not updating, we are sure we would not see broadening. Currently, there is no strong selection to evade vaccine immunity as the virus is transmitting very nicely in vaccinated populations. Though the boosters of vaccines based on the original Wuhan-Hu-1 strain have ‘temporarily’ worked better than expected, as the virus continues to diverge, at some point that has to stop being true. We do need broader and longer-lasting immunity. In an animal (mice) study, using an Omicron spike for a third dose, it is found that it better protects against Omicron than using the original spike [29]. Undoubtedly, there is inertia due to antigenic imprinting. But just because an immune system is slow to turn does not mean it would not eventually or that we should not try. Recently, Moderna has published phase II/III results of their bivalent vaccine candidate mRNA-1273.211 (equal mRNA amounts of ancestral SARS-CoV-2 and Beta variant spike proteins) in a preprint [30]. This bivalent Beta booster was better at neutralizing Omicron than the ancestral booster alone.

Yet another option is to work on developing a multi-antigenic vaccine that has antigens of different variants to increase the breadth of the immune response. There is an urgent need to develop ‘pan-coronavirus’ or ‘pan-sarbecovirus’ vaccines considering the unpredictability of the SARS-CoV-2 virus evolution. These vaccines may not only be effective against the current variants but future variants too. Although almost 20 different groups of researchers are on the job [31], it is a complex process and not everyone is sure of its ultimate success.

In conclusion, to tackle this complex and unpredictable phase of the pandemic, the development of new Covid-19 vaccines should be the global priority. The rise of SARS-CoV-2 variants and evidence of immunological interference like antigenic imprinting and diminishing role of T cell immunity underscore the continued need for next-generation preemptive vaccines that elicit broader immunity against existing and future SARS-CoV-2 VOCs.

Declaration of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Authors contribution

VMV and PK both have substantially contributed to the conception and design of the article and interpreting the relevant literature. Both have been involved in writing the article and also revision of the same.

Additional information

Funding

The authors received no direct funding for this research