Oncolytic Measles Virotherapy Does Not Legitimize Opposition To Measles Vaccination

Abstract

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been falling in large part due to public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of the current paper is to address a new misinformed anti-vaccination argument, that measles immunity is undesirable because measles virus is protective against cancer. Having worked for many years to develop engineered measles viruses as an anticancer therapies, the authors of this review have concluded first that measles is not protective against cancer and second that its potential utility as a cancer therapy will be enhanced, not diminished, by prior vaccination.

For the past 20 years the authors of this minireview and position statement have been developing engineered versions of measles virus as potential cancer therapies. These viruses have been shown to infect and kill cancer cells and to boost the immune response against the tumor. Unfortunately, our work is now being inappropriately and incorrectly cited by anti-vaccine campaigners to argue against measles vaccination.

The question that prompted this review:

Recently, one of us received an email message from an exasperated teacher, subject “please, please make a statement about MMR (measles, mumps, rubella) vaccine”. The message read as follows:

“I’m a teacher and your supportive opinion would go a lot further than all the numbers I can throw at parents. They see your work and make some judgement about measles being protective against cancer, therefore do not vaccinate their kids. Please answer. Do you advise families [to] immunize their children on schedule?”

The answer:

The answer is an unequivocal YES, we do very strongly advise families to immunize their children on schedule. Measles is a serious infection capable of killing infected children. It caused 110,000 deaths worldwide in 2017^{1, 2}. Vaccination protects against measles and has been administered to over a billion people with an exceptional safety record. There is no evidence that measles infection can protect against cancer. Our studies using engineered measles viruses to treat cancer have shown the best outcomes in people who have been vaccinated and our current approaches are fully geared to this group of cancer patients.

We are dismayed to learn that our work is being cited in opposition to MMR vaccination and are therefore taking this opportunity to review the key pertinent facts about measles, measles vaccination and measles as an experimental cancer therapy that support this position.

The Facts about Measles

Measles spreads in respiratory droplets and is the most transmissible virus known (“coughs and sneezes spread diseases”)^{3, 4}. The R0 (numbers of people in a susceptible population that will be infected by a single person with measles) is 15-20, much higher than the R0 of Ebola (1.5 to 2.5) or Influenza (1.4 to 4)^{5, 6}. After an incubation period of 9 to 11 days the virus causes a severe head cold (conjunctivitis, swollen eyelids, photophobia, hacking cough and nasal discharge) with associated fever, irritability and general malaise which lasts 3 to 4 days, then gives way to a blotchy maculopapular rash which starts on the forehead, spreads down over the face, neck and trunk to the feet and lasts around 6 days.

Most children infected with the virus recover completely and develop lifelong immunity to reinfection. However, recovery is not guaranteed, and the infection can lead to several serious complications which are collectively responsible for the high mortality and long term morbidity of measles^{7, 8}.

If the virus spreads more extensively in the body it can cause bronchitis, bronchiolitis, viral pneumonia, corneal ulceration and blindness, myocarditis, hepatitis and encephalomyelitis. Also, and not widely appreciated, measles in pregnancy can result in devastating loss. In one study of 58 pregnant women with active measles infection, 15 women developed pneumonia, 13 had premature deliveries and 5 spontaneous abortions^{9, 10}.

Aside from causing damage to infected tissues, measles is powerfully immunosuppressive due to direct lymphocyte infection/killing as well as inhibiting the proliferation of uninfected lymphocytes^{4, 11, 12}. Secondary bacterial pneumonia and bacterial otitis media are therefore frequently encountered during measles. Immunosuppression may persist for weeks after measles resolution, as evidenced by impairment of the delayed type hypersensitivity reaction to intradermal tuberculin, and patients are therefore at substantially increased risk for tuberculosis reactivation, and other opportunistic infections during this time¹³. One to three in 1000 children contracting measles will develop encephalitis concurrent with measles infection¹⁴, of whom 10-15% will die and a further 25% develop long term neurological damage¹⁵. Additional post infectious complications include a progressive fatal encephalitis with onset 1 to 6 months post infection in 1 in 1000 children)¹⁵ compared to 1-2 in a million following live virus vaccination¹⁶ and 1 in 25,000 children with measles will develop subacute sclerosing panencephalitis with typical onset many years later¹⁴. In the USA, this figure has been reported to be as high as 1 in 1,367 for children younger than 5 years old¹⁷.

Because of differences in the availability of supportive care and risk of exposure to serious opportunistic pathogens, overall measles mortality varies country to country from 0.1 to 3.0%. In 2017, 110,000 people died from measles, mostly children under age of 5 years ¹. But even the lower of these mortality numbers is frightening when caring for an infected infant, and fully justifies the international effort to eradicate the disease.

Before measles vaccination, epidemics in large population centers came every 2 to 3 years and 95% of children were immune by age 15. New epidemics therefore almost entirely impacted younger children. This was fortunate because measles in adults is more severe than measles in children.

The Facts about Measles Vaccination

The goal of vaccination is to induce protective levels of circulating anti-measles antibodies. This is achieved through subcutaneous injection of a small dose of a replication competent strain of measles virus attenuated and rendered non-pathogenic by years of tissue culture passage and adaptation on a variety of cell substrates⁵.

The strain of measles virus most widely used for vaccination was originally isolated from the throat of an 11 year old boy named David Edmonston in 1954^{18, 19}. In the 70 years since Edmonston (Edm) lineage viruses were first used for vaccination, there has never emerged a wild type measles virus that can evade the neutralizing anti-Edm antibody response. Early Edm vaccines were less stringently attenuated than those currently in use and were prone to cause a mild measles like illness (reactogenic). Newer vaccine strains are extremely well tolerated causing only minimal and short-lived side effects in vaccines⁶.

Given that autism is often first manifest around the time of measles vaccination, reports of autism arising shortly after the first exposure to a measles vaccine are inevitable. But detailed statistical analysis of the temporal relationships of vaccination to autism onset provides no support for a causal connection, not is there a plausible mechanistic basis to even suspect a connection^20–23.

The best way to protect a population from measles virus is to maintain immunity levels greater than 95% by vaccinating as many children as possible as soon as they are old enough to respond to the vaccine^{24, 25}. If vaccine coverage drops below a critical threshold level, the number of susceptible children in a population can rapidly rise to the point at which a measles epidemic can easily be sustained, whereupon most of those individuals not vaccinated will likely succumb to measles infection and population immunity will temporarily be restored to protective levels.

In the face of an advancing epidemic, nonimmune individuals can be speedily protected, either by administering pooled human gamma globulin within 6 days of virus exposure or by vaccination any time before, or up to 3 days after virus exposure²⁶. But the logistics of “last minute” vaccination during a rapidly spreading epidemic are problematic.

With high enough global vaccine coverage, it should in theory be possible to eradicate measles and the WHO is aggressively pursuing this goal ⁵. However, there are significant barriers to achieving the levels of vaccine coverage required for global eradication that will need to be addressed if this dream is ever to be realized.

The first major barrier has to do with the timing of measles vaccination. Newborn children are generally protected from measles by antibodies that they acquire transplacentally from their mothers in utero²⁷. Unfortunately, in addition to being resistant to measles infection, the babies of measles-immune mothers are also resistant to measles vaccination because their transplacentally acquired antibodies neutralize the vaccine. For this reason, vaccination is not initiated until 12 to 15 months of age in countries with low measles incidence versus 9 to 12 months of age in countries with higher incidence²⁸.

These timelines create a “window of vulnerability” for children younger than 9 to 12 months once they have lost the protection of their maternally acquired antibodies which disappear from the bloodstream with a half-life of only one month. For this reason, one of the major goals of measles vaccine research is to develop a vaccine that will be effective even in the presence of maternally acquired antimeasles antibodies and which can therefore be effectively deployed at a younger age ^{27, 29, 30} In this regard we have recently engineered the surface proteins of the Edm vaccine strain to create a derivative virus that is not only effective in the presence of antibodies from vaccinated mothers, but which also retains the ability to stimulate the production of antibodies capable of neutralizing wild type measles viruses (Muñoz-Alía and Russell, unpublished).

The second major barrier to measles eradication is simply getting people to vaccinate their children. This can be particularly difficult in areas of conflict (e.g. war zones) where the cost and logistics of supplying the vaccine can be highly problematic³¹. But perhaps even more challenging than war zone logistics is the recent epidemic of unfounded and irrational anxieties regarding vaccine-induced autism which is driving an ever-increasing number of parents to refuse permission for their infants to be vaccinated^{32, 33}.

And now, adding insult to injury, the additional argument of measles infection being “good for cancer” appears to be gaining traction.

The Facts about Measles Virotherapy

Experiments of nature, such as the spontaneous regression of a large retroorbital Burkitt lymphoma coincident with measles, point to the possibility of using measles as an anticancer drug³⁴. However, it is important to emphasize there is no evidence to suggest that natural measles infection can protect against the later development of cancer.

Regarding the development of measles as an anticancer drug, the naturally occurring (wild type) virus is a dangerous pathogen, not suitable for use as a cancer therapy. We and others therefore decided to determine whether attenuated measles strains belonging to the Edmonston vaccine lineage had anticancer potential and the result of these endeavors is now an extensive literature demonstrating that this is indeed the case^{35, 36}.

Attenuated Edmonston lineage measles viruses are selectively destructive to cultured human cancer cells of many different tissue origins, and to human tumor xenografts grown in immune deficient mice³⁷. Various “therapeutic” genes have been added to the measles genome to further enhance its “druggability” and to increase its potency as an anticancer therapy. Moreover, technologies have been developed that allow the exquisite targeting of measles virus tropism so that it can now be engineered for highly specific infection and killing only of unwanted cancer cells^{38, 39}. At least three different measles virus constructs have to date been administered to more than 150 cancer patients in clinical trials and the results from those studies have been highly encouraging^{35, 36, 40–43}.

In one study at Mayo Clinic, a 49 year old woman with multiple myeloma that had become refractory to all available therapies (including two stem cell transplants) had a remarkable response to a single intravenous infusion of measles virus³⁵. After a short-lived febrile reaction to the virus infusion, all 5 of her rapidly growing plasma cell tumors resolved completely and her bone marrow was completely free of myelomatous plasma cells. She did have a focal disease recurrence at 9 months, then again at 2 years post measles virus infusion but both of these relapses responded briskly to local radiation therapy and her disease remains in complete remission today, 5 and a half years later, having received no additional myeloma drug therapy.

While several additional cancer patients have responded favorably to single agent measles virus therapy since that time, we have not yet seen a comparable durable complete remission. Careful analysis of the extensive correlative datasets amassed on this best-responding patient revealed that her tumor carried a very high mutational burden, she had a high baseline frequency of measles-reactive and tumor-reactive T cells, and, despite a history of recent measles vaccination (after her first stem cell transplant), she had virtually undetectable circulating antimeasles antibodies (Russell and Packiriswamy, unpublished).

All of these parameters are now believed to have acted in concert to shape the favorable response to measles therapy in this patient; the absence of antimeasles antibodies allowed the virus to access sites of tumor growth via the bloodstream, and to mediate inflammatory killing of myeloma cells in situ; the abundant antimeasles T cells were rapidly recruited to infected tumors where they further boosted the killing of measles infected cells, thereby accelerating the recruitment of a second wave of T cells specifically recognizing a range of myeloma specific tumor antigens, and therefore capable of killing residual uninfected myeloma tumor cells.

Thus our current perspective is that the optimal scenario for effective measles virotherapy is that the patient should, at the time of treatment, have abundant antimeasles T cells but no antimeasles antibodies. Provided the patient has previously received the measles vaccine, this ideal scenario can be achieved in the following ways: (i) by transiently depleting antimeasles antibodies pre-therapy; (ii) by using measles infected cell carriers to deliver the virus, thereby evading antimeasles antibodies^{44, 45}; (iii) by engineering an oncolytic measles virus that is no longer recognized by anti-measles antibodies^{46, 47}.

All three of the above scenarios are actively pursued at Mayo Clinic. Most advanced is the cell carrier strategy which is being evaluated in patients with ovarian cancer using fat derived autologous mesenchymal stem cells which are infected with measles virus and administered immediately into the peritoneal cavity^{44, 45} (NCT02068794) . In addition to this approach, a third generation oncolytic measles virus, resistant to anti-measles antibodies, will shortly be advanced into the translational pipeline (Russell and Muñoz-Alía, unpublished).

Conclusion

To summarize, measles is a very serious, highly transmissible, and potentially deadly virus infection which, despite intensive efforts to achieve global vaccination coverage, was still responsible for over 100,000 deaths in 2017¹. Recent epidemics in US and European cities where vaccination coverage is low provide a harsh reminder for the need to maintain protective levels of immunity across the entire population. Newer vaccines are being developed so that infants can be vaccinated before they lose the protection afforded by antibodies acquired transplacentally from their mothers. Measles virotherapy should not be used as an argument in opposition to measles vaccination because the most promising approaches currently being developed are designed to give superior outcomes in vaccinated versus unvaccinated individuals.