Exploit T cell Immunity for Rapid, Safe and Effective COVID-19 Vaccines

KEYWORDS:

• COVID-19
• SARS-CoV-2
• coronavirus
• vaccine
• T cell
• antibody
• T cell epitope

1. Opinion

The scientific response to the SARS-CoV-2 virus outbreak has been nothing short of breathtaking. Within 7 months of virus discovery, over 75,000 virus isolates around the world were sequenced and widely shared; epidemiologists tracked global virus spread and provided real-time information to guide government responses; immune analyses began to uncover mechanisms of protection and explain differential clinical outcomes; tens of virus- and host-directed druggable targets were identified among FDA-approved and other drugs in preclinical and clinical development; several small molecule, monoclonal antibody, and convalescent plasma therapeutic clinical trials began, and a number of vaccines have entered into clinical testing. These unprecedented achievements are a silver lining in the harrowing pandemic that has claimed the lives of more than 1 million people to date, and stressed, and in some cases overwhelmed, healthcare system capacity while also disrupting world economies and the social connections that make us human.

Developing a vaccine to protect against infection is critically important to global recovery. Although the antibody-driven vaccine strategy adopted immediately by several labs, companies, and funders may be straightforward, we argue that vaccine developers should proceed rapidly while also being mindful of safety and efficacy. While that approach is surely rational based on past experience, there are now indications that antibodies wane with time, and that there may be unexpected barriers to the successful engagement of humoral immunity against the virus. The urgency of the situation calls for pursuit of multiple paths to a safe and effective vaccine. Emphasis on one approach, while setting aside others, is no small gamble. We suggest that there are several excellent and historical reasons to consider a T cell-focused approach as well as the antibody-focused approach.

Past experience suggests that one way to develop a vaccine is to implement a simple formula: to produce an immunogen that elicits antibodies that prevent virus binding and fusion with host cells. This is the approach that is associated with vaccines against viruses that are licensed and commonly accepted. It is the method par excellance to stimulate immunity that prevents not only death but also illness. Hence, the SARS-CoV-2 spike glycoprotein is the center of a massive effort to discover formulation and delivery parameters that will safely and effectively prevent disease and transmission.

Early on in the pandemic, there was hope that SARS vaccine candidates in development may protect against COVID-19. SARS-CoV-2 and SARS-CoV-1 spike protein sequences are approximately 77% homologous. They target the same cell entry protein, angiotensin-converting enzyme 2 (ACE2), and are 73% homologous in the receptor-binding domain (RBD). However, the SARS-CoV-2 RBD forms more contacts with ACE2 compared to SARS-CoV-1 RBD, suggesting that their neutralization determinants differ [1]. As antibody–antigen interactions are exquisitely specific, a vaccine strategy that relies on cross-neutralization is uncertain. There are conflicting data for the ability of human convalescent SARS and COVID-19 sera to cross-neutralize [2,3]. Thus, it is generally recognized a spike glycoprotein vaccine must be based on the SARS-CoV-2 antigen, especially if the plan is to elicit neutralizing antibodies to the RBD.

The spike glycoprotein strategy is bolstered by critical information learned in the last decade how to focus antibody responses to neutralizing sites of class I viral fusion proteins by stabilizing them in specific, pre-fusion conformations. Off-target, non-neutralizing antigenic sites on the post-fusion state are diminished when constraints on structural rearrangements are imposed using recombinant engineering. This approach has been applied to RSV, HIV, influenza, Ebola, SARS, and MERS. In the case of RSV, preclinical studies in mice and macaques showed that pre-fusion stabilized F protein raises neutralizing responses to the level observed in natural infection in humans [4]. A proof-of-concept pre-F vaccine phase I clinical trial reported neutralizing activity against pre-F at levels considerably greater than found for other F protein vaccines and an RSV human challenge model [5]. Thus, new protein engineering approaches may lead to the production of effective immunogens for antibody-driven vaccines against SARS-COV-2.

But the approach is not without risk: antibody-virus complexes may confer virus with another portal of entry into host cells and exacerbate disease. Recent work showing vaccine-induced antibody-dependent enhanced disease (ADE) after viral infection suggests caution with a spike glycoprotein-focused approach, and this concern has also been raised in the context of the COVID-19 pandemic [6]. It is encouraging that no immune-enhanced lung pathology was observed in a macaque challenge study of the ChAdOx1 SARS-CoV-2 spike vaccine, which recently completed a Phase I/II clinical trial [7], although more work will be needed to address the ADE concern in a clinical setting. Notwithstanding this potential risk, the spike glycoprotein vaccine strategy is rational, and it is anticipated that ADE will be assessed during clinical development. At the same time, it is important not to lose sight of the potential for other types of vaccines, such as T-cell-epitope driven vaccines that stimulate cellular immunity.

Several lines of evidence point to the importance of cellular immunity to protecting against severe COVID-19 [8]. For example, T cell responses are known to protect against severe infection and re-infection in animal coronavirus models [9]. In other viral infections such as severe influenza, both CD4⁺ and CD8⁺ T cell memory, which can be generated by vaccination, can protect against severe viral disease in humans [10,11]. Current clinical studies of COVID-19 disease also suggest that cellular immunity contributes to protection from COVID-19: low CD4+ T cell counts are associated with worse outcomes and exacerbation of disease [12]. Development of ARDS has been associated with higher viral loads and high antibody titers [13–15]. Furthermore, in SARS infection, virus-specific CD8+ T cells were shown to protect against ARDS [16]. Early intervention by CD4+ and CD8+ T cells can reduce intracellular replication and macrophage activation that lead to ARDS pathology in MERS and SARS [17]. Furthermore, unlike B cell responses to SARS CoV, the T cell response is long-lasting [18].

Although T cell-directed vaccines may not prevent infection, they could mitigate morbidity to reduce hospitalizations and consequently demands on limited space, supplies and staff. Reduced disease severity as an endpoint may have significant impact on public health, as exemplified by rotavirus vaccination, which dramatically reduces hospitalization and emergency room visits associated with gastroenteritis [19]. Moreover, T cell-directed vaccines stimulate immune clearance mechanisms that avoid antibody-dependent enhanced disease and that may provide immune memory capable of stemming transmission of future emergent coronavirus before viral spread reaches pandemic, even epidemic, proportions.

Furthermore, investment in T cell-directed vaccines may lead to the development of vaccines that can simultaneously target SARS-CoV-2, SARS-like viruses and potentially other betacoronaviruses. SARS-CoV-2 and SARS-CoV-1 conserved T cell epitopes in various antigens have been predicted using immunoinformatics and identified among T cell epitopes recognized by convalescent and naïve donors, suggesting that some regions are critical to viral fitness and are unchanging despite continuous evolution [20,21]. Vaccines containing such epitopes may induce memory T cells that could recognize betacoronaviruses yet to emerge after undergoing convergent evolution similar to SARS-CoV-1 and SARS-CoV-2. Naïve donors have also recognized SARS-CoV-2 T cell epitopes, suggesting cross-conserved memory T cells induced by exposure to common cold coronaviruses may be circulating in some individuals [22–24]. Thus, T cell memory may be available to boost immune responses against a SARS-CoV-2 epitope-driven vaccine. Notably, in the quest for a universal influenza vaccine, the BiondVax T cell epitope vaccine was the first to reach efficacy trials, outstripping traditional hemagglutinin-based strategies that have otherwise received more attention in the scientific community.

Despite the focus on antibody generating vaccines during the COVID-19 pandemic, other types of vaccines may also succeed in providing critical protection, and there are many reasons why the time is ripe for T cell-directed vaccine development. Over several years, critical pieces of the puzzle have come together. Highly accurate in silico T cell epitope predictors are available for rapid discovery of sequences that broadly cover betacoronaviruses and MHC class I and class II diversity in the human population [25]. Class II epitopes stimulate effector CD4 T cells that support both antibody immunity and cell-mediated immunity involving CD8 T cells that recognize class I epitopes. Epitopes with potential to induce regulatory CD4 T cells and reduce vaccine efficacy due to human cross-conservation can be avoided, also with immunoinformatic methods. Armed with this information, whole antigen vaccines may be engineered by T cell epitope modification to broaden T cell and antibody responses or vaccines based on epitopes alone may be designed [26]. Indeed, spike vaccines may induce disease mitigating CD4 and CD8 T cell responses even though they are intended to generate antibodies that prevent infection. However, the T cell response to SARS-CoV-2 is broad and T cells recognize epitopes sourced from other antigens that may elicit higher quality T cell responses.

As noted above, several vaccine formulations and platforms are capable of supporting epitope-induced immunogenicity and protection. Preclinical vaccine immunogenicity can be assessed in HLA transgenic mouse models. Immune monitoring methods, including multi-parameter flow and mass cytometry and gene expression profiling, can be used to define T cell signatures of protection and develop assays for assessing immune endpoints in clinical trials, although the lack of a clear regulatory path to licensure in the absence of a validated assay that predicts protection remains a non-trivial hurdle.

Some may question the feasibility of a T cell-directed vaccine strategy. Apart from the tuberculosis vaccine Bacille Calmette–Guérin (BCG), no vaccine that relies primarily on a T cell response to protect has been licensed. ‘But it was never done!’ did not stop scientists in wartime from achieving epic goals once thought improbable. Urgent necessity has always been known to accelerate scientific development. We are fighting a war against SARS-CoV-2 and we suggest that this is an opportunity to mobilize against COVID-19 with a vision that capitalizes on our collective knowledge, skills, and ingenuity. Alongside antibody generating vaccines, T cell-directed vaccines should be pursued, in similar formulation and delivery platforms that are currently under study with spike glycoprotein, including nucleic acid, protein, and vectored formats. If we develop T cell-directed vaccines with the same vigor that is being devoted to spike glycoprotein, we are more likely to succeed in the battle against SARS-CoV-2 and may even develop vaccines that are ready to protect future generations against other pathogenic novel coronaviruses as they are certain to emerge and threaten humanity in the future.

2. Expert opinion

We, humans, are facing an unprecedented opportunity to demonstrate our collective ability to confront the global crisis brought on by SARS-CoV-2. The COVID-19 pandemic calls for intelligence, ingenuity, compassion, and collaboration. Scientists have heeded the call, sharing information and publishing scientific results at a rapid pace. Vaccines are being developed with a speed that was heretofore not thought to be possible. In the scientific context, we can affirm that humans have risen to the occasion. And, as with every crisis, we are called upon to surmount obstacles that are man-made, such as deliberate dissemination of falsehoods, exaggerated claims and sheer cronyism in the distribution of sizable governmental investments that would normally have been subjected to careful scrutiny and scientific review. These events have contributed to a significant decline in vaccine confidence, which worsens with every subsequent acrimonious statement by politicians. It is our opinion that scientists must cleave to the truth, which now includes substantial scientific evidence that immune response by T cells contributes to protection against severe disease, not only in the context of previous pandemics such as pandemic Influenza H1N1 2009, but also, thanks to the work of many immunology researchers, to protection against SARS-CoV-2. In addition to insisting on dissemination of solid science, we must also advocate for vaccines that are both safe and effective. The leadership of Operation Warp Speed would do well to consider a Plan B, since Plan A appears to be monolithic in its approach to vaccine development. Simply ‘checking the box’, accelerating vaccines rapidly towards distribution despite concerns about safety and efficacy, is not the right approach. Science must prevail, and to that end, we offer our encouragement and support to scientists and vaccine developers around the world who are actively working on a rapid, safe and effective “Plan B”.

Declaration of interest

L Moise is an employee of EpiVax, Inc., a privately owned biotechnology located in Providence, RI. A S. De Groot is a senior officer and shareholder of EpiVax, Inc., a privately owned biotechnology located in Providence, RI. William D. Martin is a senior officer and shareholder of EpiVax, Inc., a privately owned biotechnology located in Providence, RI. LM, WDM, and ADG acknowledge that there is a potential conflict of interest related to their relationship with EpiVax and affirm that the information represented in this paper is original and based on unbiased observations. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are developing a vaccine against SARS-CoV-2 that is now in advanced clinical trials. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We are grateful to our dedicated team that shares this COVID-19 T cell-directed vaccine vision: Christine Boyle, Dominique Bridon, Chris Eickhoff, Leo Einck, Andres Gutierrez, Bethany McGonnigal, Lauren Meyers, Michael Princiotta, and Frances Terry.

Additional information

Funding

This paper was not funded.